4^th International Conference on Medicinal Chemistry & Computer Aided Drug Designing November 02-04, 2015 Atlanta, USA

Biography:

Jetze J. Tepe was awarded a PhD from the University of Virginia in 1998 and joined the laboratory of Prof. Robert M. Williams at Colorado State University as a post-doctoral researcher. In 2000, he joined the faculty at Michigan State. Research in the Tepe lab has been focused on the development of new heterocyclic reactions, and biological evaluation of novel heterocyclic natural products and analogues thereof, with a special emphasis on the NF-kappaB signaling pathway and the proteasome.

Abstract:

Natural products isolated from plant, animal or fermentation has long been the main source for compounds used in the chemotherapeutic intervention of cancer. However, in the later part of the 20th century, the advances of combinatorial chemistry have taken center stage in the drug discovery process and natural product synthesis took a temporary backseat for these new chemical processes. Combinatorial techniques and compound repurposing have resulted into large libraries in a very cost-efficient manner that can be screened for their biological activities against a desired target. Although cost-effective, these libraries suffer from a lack of diversity with respect to the structural complexity, stereochemistry and chemical space. In addition, the enforcement of restrictions of structural complexity and “drug ability rules”, further narrows the chemical space and thus limits the discovery of novel drug-target interactions. The goal of our program is to discover mechanistically distinct drug-target interactions by generating small libraries with high levels of structural diversity. Our approach is to simulate the structural complexity found in natural products and translates this into structurally diverse abridged scaffolds. Phenotypic screening of these abridged scaffold libraries followed by target identification resulted into two mechanistically distinct classes of proteasome inhibitors. In today’s presentation we will discuss this approach and the ability of these agents to overcome acquired drug resistance and effectively modify the onset of various diseases, such as multiple myeloma and rheumatoid arthritis, in vivo.

Biography:

Dr. Kal Ramnarayan (Dr. Ram) is the Founder, President, Chief Scientific Officer of Sapient Discovery. Previously, Dr. Ramnarayan Co-founded Structural Bioinformatics, Inc and Cengent Therapeutics, Inc. As part of the senior management team, he participated in raising more than US$ 50M. His technology leadership results in several leads for targets like ALF, PTP1B, SHP-2, DER, TNFR, Her-2, ZAP-70, IKKB, CD45, NY2R amongst others. He has had several successful grants from DARPA and SBIR. He has collaborated extensively with GSK, Novartis, J and J, DuPont, several Japanese, European and American companies in projects for lead discovery. Prior to Structural Bioinfofmatics, Inc., Dr. Ram was Head of Computational Chemistry at ImmunoPharmaceutics Inc., where he designed numerous drug leads, including highly specific endothelin-A receptor antagonists. This became Sitaxsentan, currently in Phase III clinical development by Encysive Pharmaceuticals. Dr. Ramnarayan holds a PhD in molecular biophysics from the Indian Institute of Science, Bangalore and has multiple papers and patents and several other patents pending. He is on the Advisory Board of the IBM BlueGene Initiative, Strand Genomics, Polyclone Bioservices and Keck Research Institute. He is on the Editorial Board of Current Proteomics. Dr. Ramnarayan is also Co-founder and Director of Focus Synthesis, LLC, in San Diego.

Abstract:

With the goal of saving costs and time, the trend now is to outsource crucial components of drug discovery. While this seems to work in labor-intensive tasks such as chemical synthesis, GMP manufacturing, animal studies and clinical work, it is not always easy to find outfits for lead discovery with reliable and proven capabilities. This is becoming an important need for Pharma and Biotech companies since there are still large numbers of protein targets involved with several disease classes yet to be exploited. The abundance of potential drug targets is a challenge for the pharmaceutical and biotech companies that have to focus their resources. At least 50% of all targets that go into high-throughput screens do not generate significant leads and hence other cost-effective technologies are required to generate novel, patentable lead molecules. We have developed a structure-based approach to develop lead molecules in 60 to 90 days, which has resulted in validated lead molecules for a diverse set of drug targets. We utilize this lead generation technology, Genes to Leads®, in collaborative drug discovery project with universities, Pharma and Biotech companies as a highly costeffective means for augmenting their drug discovery pipelines. Essential ingredients of the technology are, X-ray crystallography, protein modeling, virtual screening, docking and scoring. In this presentation we will discuss our technology with specific application examples.

Biography:

Joana Marto has a Masters degree in Pharmaceutical Sciences by the Faculty of Pharmacy of the Lisbon University (2010). Nowadays she is doing her PhD thesis by the iMed.ULisboa (Research Institute for Medicines) and Laboratórios Atral S.A. in pharmaceutical innovation. This program allows the students to acquire core and transferable skills in the field of pharmaceutical tecnhology. Her PhD thesis will focus on the development of new pharmaceutical dosage forms for topical application. Also Joana taught laboratorial classes of Galenic and Dermopharmacy in Faculty of Pharmacy, University of Lisbon.

Abstract:

Psoriasis and atopic dermatitis diseases have an excessive amount of elastase in peripheral blood neutrophils and epidermal plasminogen activator. The high levels of this enzyme inactivate the endogenous inhibitor barrier thus, the search for new human neutrophil elastase (HNE) inhibitors are required. This work presents a novel HNE inhibitor which was carried on a novel nanoparticulate system. The present study aims to develop and characterize a novel starch-based nanoparticulate carrier system (StNC) for HNE inhibitor (ER143) skin delivery The StNC were prepared by emulsion-solvent evaporation method, using Miglyol® 812 as the lipid component, Tween®80 and cetrimide as surfactants and modified starch as a polymer. The StNC was characterised in terms of particle size analysis (Malvern Mastersizer 2000 coupled with a Hydro S accessory) and the surface charge that was determined by measurements of the ζ potential (Zetasizer Nano Z in water, at 25ºC, Malvern). Permeation studies were performed using vertical Franz diffusion cells with porcine skin. Water:ethanol (70:30 w/w) were used as receptor phase for ER143. Data was expressed in cumulative amount of ER143 permeated per cm2 in order to time. Tape stripping was performed 24h after in vitro permeation studies. Stratum Corneum (SC) was separated from the epidermis and dermis using 20 tapes. An ER143 solution was used as a control. The drug content was analyzed by fluorescence methods for all of the experiments. In vivo anti-inflammatory activity was accessed using the croton oil-induced ear inflammation model in mice and StNC formulation was used as a control. The particle size obtained for StNCER143 was between 200-250 nm and showed a positive ζ potential. In vitro permeation studies thought porcine skin showed that the StNC were suitable for the delivery of ER143. After 24 h the amount of ER143 permeated was 573.2±92.7 ng/cm2 and 248.6±50.0 ng/cm2 for StNC ER143 and ER143 solution, respectively. The tape stripping assay showed that 22.7±3.9 % and 5.14±0.8 % of the drug was detected on the SC for StNC ER143 and ER143 solution, respectively, and 10.6±1.2 % and 2.2±0.5 % in epidermis and dermis for StNC ER143 and ER143 solution, respectively. Hence, StNC formulation contributed for both higher skin retention and permeation profiles of ER143possibly due to the presence of skin permeation enhancers as well as lipid content. In vivo results showed that erythema and edema were attenuated in 98% and 69% by the local application of StNC ER143 and StNC formulations, respectively, revealing a synergic effect between placebo and ER143-loaded StNC. These StNC nanocarriers are suitable for a deeper skin penetration and retention. Here we proved that starch-based nanoparticulate carrier systems (StNC) are useful as topical delivery systems, with promising in vivo results.

Biography:

José Raúl Bahena Herrera is medical student at the Escuela Superior de Medicina. Since 2013 he has been distinguished with a fellowship to work as a young researcher on the Department of Biochemistry at Instituto Politecnico Nacional; his research lines include cancer and apoptosis regulation, modulation of GPCR´s, neurodegenerative diseases such as Parkinson's disease and depression.

Abstract:

Adrenergic receptors are important targets for pharmaceutical development and physiological studies. Although several drugs have been designed as agonist/antagonist for these receptors, the insights for rational design of highly selective molecules are still not widely described nor used. Therefore the aim for the present study was to determine the affinity and selectivity of a series of new rationally designed isoindoline derivatives with β1 / β2 adrenoceptors. We performed a global and local reactivity evaluation of the best ligands with β2 adrenoceptor in order to understand the selectivity of the binding pocket. The results of the in silico experiments suggest that our molecules might be metabolized by CYP450 and they are in agreement with the Lipinski’s rule of five; the docking studies show that the ligands interact with the orthosteric site of β2-adrenoceptors and with the orthosteric and allosteric site of β1 adrenoceptor with more selectivity for the first one. The ex vivo results in the isolated guinea pig trachea model indicates that EC50 for the molecule MD2p13-16 was 2.39 x 10-8 M, with a ΔG of -10.8 ± 1.2 Kcal/Mol. Finally Molecule MD2p13-16 have a higher potency in comparison to albuterol for concentrations 1 x10-10, 1 x 10-9.5, 1 x10-9 and 1 x10-8.5 M; all the above information allows us to propose that the designed drug works as a partial agonist of β2-adrenoceptor and according to Hill's equation we can associate a phenomenon of negative cooperativity.

Biography:

Dr. Wen has completed her PhD at the age of 32 years from National Tsing Hua University in 1993. She is the researcher of Biomedical Technology and Device research Laboratories,Industrial Technology Research Institute. She was interested in organic synthesis and asymmetric synthesis and applied these technologies in the drug optimization

Abstract:

ITRI pharmaceutical optimization technology division found a uricosuric nature compound, oxyresveratrol, as a potential gout treatment agent. The pharmacological effect of oxyresveratrol is limited by low exposure of the compound associated with rapid metabolic modification and excretion. A possible approach to overcome the hurdle is to develop oxyresveratrol pro drugs. In order to overcome the PK weakness of oxyresveratrol, some functional groups have been decorated onto the metabolic weak point of the molecule, aimed to generate a fit for purpose prodrug molecule. Twenty-nine oxyreveratrol prodrugs have been synthesized by two different synthetic pathway. The Cmax and AUC of the ether linkage oxyresveratrol prodrug OP-0108were two-fold more than that of oxyresveratrol compared with equal molar dose strength.

Biography:

Ernesto Daniel Guevara Avendaño is medical student at Escuela Superior de Medicina at Instituto Politécnico Nacional. He is a young researcher at Biochemistry Department since 2014. He is interested on development of new drugs on different research lines such as obesity, asthma, depression and Parkinson's disease. His actual work is focused on drug design for obesity therapy.

Abstract:

Obesity is a chronic disease associated with the increase in morbility of diabetes, hypertension, metabolic syndrome and cancer. Current drugs used in therapy stimulate the central nervous system and can cause unwanted sympathomimetic effect that may limit the use of these, here is the importance of research for new drugs with better defined target such is the case β3-adrenoceptor (β3AR). The purpose of studying β3AR is its participation in thermogenesis and lipolysis. The aim of the present work was to develop a series of ligands with higher affinity for the β3AR and characterize their activity in an in vitro and in vivo model. The in silico results suggest that the best molecules were IsF6S-15, IsF8R-15, IsF8S-15 and IsF9-15 satisfying the Lipinski's rules of 5. The molecule IsF1-15 was synthesized and characterized by NMR, IR and Mass spectrometry, then was tested in an in vivo model of obesity with male C57BL/6 mice. In vivo experiments showed that molecule IsF-15 have an significant effect on the decrease in weight (p<0.05), very similar to the reference, clobenzorex, which is currently used in México, other parameter that was modified was the triglycerides levels that had a significant decrease even more than clobenzorex. The glucose levels were not modified compared with the hyper control, this suggests that IsF-15 do not have significant effect on glucose and also cholesterol levels were similar to the control group. These results lead us to continue the research for phenylethylamine derivatives and their effect on β3AR on obesity therapy.

Biography:

Mutasem Taha has completed his PhD at the age of 28 years from Lougborough University in the UK. He is Professor at the Faculty of Pharmacy-University of Jordan. He has published more than 100 papers in reputed journals and he has authored 2 books and has 4 patent on his name. He has been serving as an editorial board member of repute.

Abstract:

The significant role played by docking algorithms in drug discovery combined with their serious pitfalls prompted us to envisage a novel concept for validating docking solutions, namely, docking-based comparative intermolecular contacts analysis (dbCICA). This novel approach is based on the number and quality of contacts between docked ligands and amino acid residues within the binding pocket. It assesses a particular docking configuration on the basis of its ability to align a set of ligands within a corresponding binding pocket in such a way that potent ligands come into contact with binding site spots distinct from those approached by low-affinity ligands and vice versa. In other words, dbCICA evaluates the consistency of docking by assessing the correlation between ligands' affinities and their contacts with binding site spots. Optimal dbCICA models can be translated into valid pharmacophore models that can be used as 3-D search queries to mine structural databases for new bioactive compounds. dbCICA was implemented to search for new inhibitors of candida N-myristoyl transferase as potential antifungal agents and glycogen phosphorylase (GP) inhibitors as potential antidiabetic agents. The process culminated in five selective micromolar antifungal leads and nine GP inhibitory leads.

Biography:

María Laura Lavaggi completed her PhD in Medicinal chemistry in 2009 at the Facultad de Química, UdelaR, Uruguay. She has been responsible of research grants involving anticancer prodrug design and published several papers on the area. Also she has mentored graduate students thesis and at the moment one Master´s degree thesis. At the moment she is involved in different research projects some of them based on the development novel anti-cancer and anti-neurodegenerative agents and ecotoxicology involving genotoxic damage of residual pesticides.

Abstract:

Solid tumors contain hypoxic regions, which confers resistance to radiation and chemotherapy, but in turn offers an attractive difference between normal and tumor cells that can be exploited to obtain selective drugs directed to specific targets on hypoxic cells. Hypoxia induces changes in gene expression profile through the induction of a transcriptional factor called hypoxia-inducible factor, HIF-1. This protein activates the transcription of genes related to cell survival. An interesting strategy for the development of antitumor agents is the use of prodrugs, which after selective bioreduction under hypoxic conditions, interact with DNA affecting the binding site of HIF-1. In this work we have designed derivatives of amino-phenazine 5,10-dioxides as potential prodrugs which bind selectively to the 5'-3'-ATACGTG and thereby prevent interaction with HIF-1. To determine the possible interaction mode, molecular docking calculations and molecular dynamics simulations were carried out. Some of the derivatives proposed interact with the region of interest and also intercalate into DNA with good affinity. The synthesis of compounds that show an adequate degree of affinity with the intended target has been performed, via nucleophilic substitution to formaldehyde followed by the addition of aliphatic alcohols that react with the imino intermediate, generating compounds with different degree of side branching, with yields moderate to good.

Biography:

Mitsuji Yamashita was born in 1944 and has completed his PhD at the age of 27 years from Nagoya University, Japan, and postdoctoral studies from Iowa State University, USA. He was a visiting professor of University of Massachusetts at Amherst, USA, and a visiting researcher of Oxford University, UK, in 1994. He was promoted to be a professor of Shizuoka University, Japan, in 1996 and retired at the age of 65 years to be a professor emeritus of Shizuoka University, Japan. His research field is now focused on medicinal materials based on chemistry of carbohydrates and phosphorus compounds regarding phospha sugar antitumor agents and sugar dendritic Gd-DTPA MRI contrast agents for innovating in cancer therapy. He has published more than 180 papers and patents as well as four books.

Abstract:

Novel multiple type and wide spectral low-molecular-weight molecular targeted antitumor agents of phospha sugar derivatives, which target IER5/Cdc25B and innovate in chemo-therapeutic treatments against various type of cancer cells, were investigated. We have developed novel synthetic methodologies for preparing phospha sugar derivatives, in which the oxygen atom in the hemiacetal ring of Haworth structure is replaced by a phosphorus moiety, and constructed their compound library, and then preclinical evaluations and mechanistic investigations have been carried out. Among the compound library of the phospha sugar derivatives, branched deoxybromo-phospha sugar derivatives (DBMPP and TBMPP) as well as some substituted phospha sugar analogues were found to exert novel, potential, and wide spectral antitumor activities by MTT in vitro evaluation method. The characterization and mechanism elucidation of these phospha sugar derivatives by flow cytometry and Western blotting showed that phospha sugars DBMPP and/or TBMPP enhanced the expression of cancer suppressors and suppressed the expression of cancer accelerators. Phospha sugar derivative TBMPP enhanced the expression of IER5 and then suppressed the expression of Cdc25B, which is the common and essential factor to act at the mitosis stage of tumor cell cycles. Therefore, phospha sugar derivatives might induce apoptosis at G2/M stage and inhibit the proliferation of various kinds of cancer cells. In vivo evaluation for TBMPP against K562 cells transplanted to a nude mouse implied successful cure of cancer. Based on the preclinical research and computer aided drug designing we are expecting that phospha sugars may be developed to be clinically useful novel antitumor agents.

Biography:

Yaser Rihan is principle scientist in Atomic Energy Authority, Hot Lab Centre, Egypt

Abstract:

An electrostatic micromachined pump is designed and simulated. The designed micropump has the advantages of flow rate controllability, self-priming, small chip size, and low power consumption. The designed micropump is simulated by the Runge-Kutta method. The flow rate of the designed micropump is considered 10 μl/min which is quite suitable for drug delivery applications, such as chemotherapy. The simulation results for the first membrane deflection with different materials and at pulsed applied voltage is introduced.

Biography:

Saima Kalsoom is a assistant professor in Quaid-i-Azam University in Pakistan

Abstract:

The function of the immune system depends in a large part on interleukins. Interleukin are a group of cytokines that were first seen to be expressed by white blood cells. The majority of interleukins are synthesized by helper CD4 T lymphocytes, as well as through monocytes, macrophages, and endothelial cells. They promote the development and differentiation of T and B lymphocytes, and hematopoietic cells .The rare deficiencies in the number of interleukins cause autoimmune diseases or immune deficiency. Hence, IL-2 holdsconsiderable promise as a therapeutic target for the treatment of autoimmune disorders. Forthe development of new immunomodulators, current therapies target IL-2 production or the IL-2signaling pathway. A small molecule inhibitor of the IL-2/IL-2Rα interaction could offer a significant improvement in immunosuppressive therapy. The present study describes the usefulness of in silico tools in identification of new IL-2 inhibitors. The identification of novel IL-2 was carried out by the steps followed both in dry and wet labs in different round of experiments. Structure based pharmacophore was designed for IL-2 inhibitors. Pharmacophore based viertual screening was performed by using ZINC and MOE databases. Hits compounds were further filtered by performing molecular docking studies. Fifty compounds were identified as hits for IL-2 inhibition. All these compounds were synthesized in wet lab. All these synthesized compounds were submitted for IL-2 inhibition assay. Results were very promising as all compounds were found to be active as IL-2 inhibitors.

Biography:

Abstract:

B-RAF is a member of the RAF protein kinase family involved in the regulation of cell growth, differentiation, and proliferation. It forms a part of conserved apoptosis signals through the RAS-RAF-MAPK pathway. V600EB-RAF protein has much potential for scientific research as therapeutic target due its involvement in human melanoma cancer. In the current work, molecular modeling study was carried out for the first time with 3D-QSAR studies by following the docking protocol on three different datasets of V600EB-RAF inhibitors. Based on the co-crystallized compound (PDB ID: 1UWJ), a receptor-guided alignment method was utilized to derive reliable CoMFA and CoMSIA models. The selected CoMFA model gives the best statistical values (q2 =0.753, r2 =0.890). With the same alignment protocol, a statistically reliable CoMSIA model out of fourteen different combinations was also derived (q2 = 0.807, r2 = 0.961). Actual predictive powers of both models were rigorously validated with an external test set, which gave satisfactory predictive r2 values for CoMFA and CoMSIA models, 0.89 and 0.88, respectively. Additionally, y-randomization test was also performed to validate our 3D-QSAR models. Contour maps from CoMFA and CoMSIA models supported statistical results, revealed important structural features responsible for biological activity within the active site and explained the correlation between biological activity and receptor-ligand interactions. Based on the developed models few new structures were designed. The newly predicted structure (IIIa) showed higher inhibitory potency (pIC50 6.826) than that of the most active compound of the series.

Biography:

Thorsten Nowak completed his Ph.D. from the University of Cambridge (UK) in the areas of aldol methodology and natural product synthesis. In 1996 he joint AstraZeneca where he worked on all stages of drug discovery in medicinal chemistry as team leader and project manager. His keen interest in new technologies motivated a career move in 2012 when he joined C4X Discovery. Since he joined C4X, Thorsten has been instrumental in expanding the capabilities of C4X into applied drug discovery. In his current role as Head of Medicinal Chemistry, Thorsten is leading the chemistry group and is responsible for all internal drug discovery efforts conducted at C4X as well as programme work with our pharmaceutical partners.

Abstract:

Orexin-1 and Orexin-2 are Class A GPCRs primarily found in the hypothalamus and locus coeruleus. These receptors have been linked to a range of different physiological functions, including the control of feeding, energy metabolism, modulation of neuroendocrine function, and regulation of the sleep−wake cycle. Importantly they are also associated with dopaminergic neurons of the ventral tegmental area (VTA) that are critical elements of the reward system. The presentation will detail the impact of a new NMR-enabled conformational design approach1on the identification and optimization of novel highly selective Orexin-1 antagonists which show significant in vivo activity. Moreover, it will be described how the detailed understanding of the experimentally determined conformational behavior of small molecule ligands when coupled with GPCR homology modeling and targeted mutagenesis (HGMP) provide novel insights into the likely pharmacophore as well as the origin of the exquisite selectivity of the described Orexin-1 antagonists.The HGMP method has been developed by Evotec in conjunction with the Oxford University to support GPCR structure-based drug discovery programs.

Biography:

Hesham Haffez has completed his master degree since 2011 from pharmacy college, Helwan University, Cairo, Egypt.Now about to get hisPh.D.degree in medicinal chemistry, Durham University, United kingdom.

Abstract:

All-trans Retinoic acid (ATRA) is widely used to direct differentiation of cultured stem cells and pluripotent embryonal carcinoma (ECs) stem cell lines into neuronal cells. EC23 and EC19 are synthetic analogues of retinoic acid (RA) differing from each other with respect to the position of the carboxylic acid group. EC23 has been shown to be a more potent inducer of neuronal differentiation than either EC19 or ATRA. In order to investigate the molecular basis of the functional difference, binding assays to RA Receptors (RAR α, β and γ, respectively) and molecular modeling studies were performed. EC50 values for EC23 are generally lower than for EC19 or ATRA on RAR-α and-β, indicating a higher binding affinity and co-activator recruitment. In silico molecular docking studies confirmed these differences in binding interactions, and showed that the carboxylic acid group of EC23 in the para-substitution creates the best fit to the ligand binding site with minimal steric hindrance, favoring the downstream binding of transcriptional co-activators. For EC19, the meta-substitution of the carboxylic acid group points away from a favorable interaction with Arg278 (RAR-γ) or create steric clashes with RAR-α/-β, resulting in interference with downstream co-activator binding activity. In comparison, ATRA shows similar protein-ligand interactions to EC23, supporting the notion that ATRA and EC23 possess similar molecular activation mechanisms. This study was able to combine chemical structures, receptor binding assay and molecular docking tools to shed light on the reported biological activity of these synthetic retinoids.

Biography:

LucíaMinini has completed her biochemistry degree at the age of 24 years from Facultad de Ciencias, UdelaR, Uruguay. She achieved a scholarship for her Master’s degree at Facultad de Química. She is involved in different research projects working on the development novel molecules as anti-cancer, anti-neurodegenerative and anti-trypanosomal agents. Besides she is studying beta-amyloid peptide’s behavior related with AD. Recently she published two articles at scientific journals.

Abstract:

Alzheimer disease (AD) represents the most prevalent neurodegenerative disorder in the world. Until now the causes of the disease have not been elucidated. The pharmacological treatment currently used for AD is based on old hypotheses that have been questioned in the last years. Unfortunately, this treatment only improves patient’s life quality but it is not efficient to cure the disease. For this reason, it is crucial to discover new targets involved in the onset of this disease. In this context, caspase-3 arises as a promising target since it has been found overexpressed in brains from AD patients during the early stages of the disease. In the present work we propose the CADD of new caspase-3 selective inhibitors, aryl-tiazole derivatives, based on reported mild but selective inhibitors of this enzyme. These derivatives bind at the substrate binding pocket and interact weakly with subsites S4-S5. It is worth noticing that although caspase-3 and caspase-7 are very similar, they contain relevant differences at subsites S4 and S5 that can be exploited in the search of selective inhibitors. Therefore, our compounds were designed to improve those interactions. Using docking and molecular dynamics simulations the inhibitors binding mode in caspase-3 and caspase-7 was determined. Results show that our novel molecules effectively interact at S4-S5 subsites in caspase-3 and at the heterotetramer interface in caspase-7. The designed compounds were synthesized and evaluated against both caspases. Those compounds with a better profile against caspase-3 were selected for studying their mechanism of action using theoretical and experimental approaches.

Biography:

Olayide A. Arodola graduated Master of Medical Science (Pharmaceutical Chemistry) with a Summa Cum Laude from University of KwaZulu-Natal and continued her PhD (Pharmaceutical Chemistry) at the University of KwaZulu-Natal, South Africa. She is a current awardee of the Golden Key International Honour Society Award 2015. She has published 3 papers in reputable journals and one of her papers won the poster award at an international conference in 2014.

Abstract:

Based on experimental data, the anticancer activity of nelfinavir, an FDA-approved HIV-1 protease inhibitor, was reported. Nevertheless, the mechanism of action of NFV is yet to be verified. It was hypothesized that the anticancer activity of nelfinavir is due to its inhibitory effect on Heat Shock Protein 90 (Hsp90), a promising target for anticancer therapy. Such findings prompted us to investigate the potential anti-cancer activity of all other FDA-approved HIV-1 protease inhibitors against human Hsp90. To accomplish this, “loop docking” – an enhanced developed in-house molecular docking approach –followed by molecular dynamic simulations and post-dynamic analyses were performed to elaborate on the binding mechanism and relative binding affinities of nine FDA-approved HIV-1 protease inhibitors against human Hsp90. Due to the lack of the X-ray crystal structure of human Hsp90, homology modelling was performed to create its 3D structure for subsequent simulations. Results showed that nelfinavir has better binding affinity (∆G = -9.2 kcal/mol) when compared to other protease inhibitors – this is in a reasonable accordance with the experimental data (IC50 3.1µM). Indinavir, saquinavir and ritonavir have close binding affinity to nelfinavir (∆G = -9.0, -8.6 and -8.5 kcal/mol, respectively). Per-residue interaction energy decomposition analysis showed that hydrophobic interaction (most importantly with Val534 and Met602) played the most predominant role in drug binding. To further validate the docking outcome, 5ns MD simulations were performed in order to assess the stability of the docked complexes. To our knowledge, this is the first account of detailed computational investigations aimed to investigate the potential anticancer activity and the binding mechanism of the FDA-approved HIV PIs binding to human Hsp90. Information gained from this study should also provide a route map towards the design, optimisation and further experimental investigation of potential derivatives of PIs to treat HER2+ breast cancer

Biography:

Babar Ali is a assistant professor in Buraydah Colleges

Abstract:

Black cumin oil is obtained from the seeds of Nigella Sativa L. which belongs to family Ranunculaceae. Seeds oil has been reported to possess antitumour, antioxidant, antibacterial, anti-inflammatory, poglycaemic, central nervous system depressant, antioxidant and immune stimulatory activities. These bioactivities have been attributed to the fixed oil, volatile oil, or their components. Seed oil consisted of 15 saturated fatty acids (17%) and 17 unsaturated fatty acids (82.9%). Long chain fatty acids and medium chain fatty acids have been reported to increase oral bioavailability of peptides, antibiotics and other important therapeutic agents. In earlier study permeation enhancement and bioenhancement of drugs has been done with black cumin oil.

Objectives: In order to recognize the mechanism of binding of fatty acids to P-gp, Linoleic acid, oleic acid, margaric acid, cis-11, 14-eicosadienoic acid and stearic acid were selected for insilico studies which were carried out using AutoDock 4.2, based on the Lamarckian genetic algorithm principle. Materials and methods: Template search with Blast and HHBlits has been performed against the SWISS-MODEL template library (SMTL). The target sequence was searched with BLAST against the primary amino acid sequence of P glycoprotein from Rattusnorvegicus.

Results: The amount of energy needed by Linoleic acid, Oliec acid, Eicosadeinoic acid, Margaric acid and Stearic acid to bind with P-gp were found to be -10.60,-10.48, -9.95, -11.92 and -10.37 kcal/mol respectively. The obtained data supports that all the selected fatty acids have contributed to inhibit P-gp activity thereby enhance the bioavailability of drugs.

Conclusion:This study plays a significantrole in finding hotspots in P-gp and mayoffer further scope of designing potent and specific inhibitors of P-gp.

Biography:

Srinu M is a researcher in University Hyderabad

Abstract:

A hybrid pharmacophore approach was deployed to design and synthesize new series of isatin- quinoline hybrids. All the new series of hybrids (6 a-l) were investigated for molecular docking study against enoyl ACP reductase enzyme. The docking study was performed on 22 newly designed isatin analogs by using Auto Dock 4.2 on the active site of crystal structure of enoyl ACP reductase enzyme (PDB ID: 4TZK). The binding modes of these analogs were calculated based on the two parameters such as binding energy and inhibition constant. The results shown that all the isatin analogs were in the range between -6.43 kcal/mol and -9.08 kcal/mol. Based on the results obtained by the docking study twelve new series of Isatin- quinoline hybrid molecules were synthesized and characterized by physical and spectral analyses (FT-IR, 1H-NMR, 13C NMR and Mass spectroscopy). According to the docking study compound 6h has highest binding affinity with a binding energy of -9.08 kcal/mol and predicted inhibition constant was 221.75 nanomolar. This compound exhibited well established hydrophobic bonds with amino acid Tyr 158 and the co factor NAD 500 in the receptor active pocket and fortunately these two are responsible for the enzyme activity. All the hybrids were evaluated for their in vitro antitubercular activity against drug resistant strains of Mycobacterium tuberculosis (MTB) by using micro dilution method and their inhibitory (MIC) and bactericidal (MBC) activity was determined. Compound 6h has the good inhibitory (0.09 mg/L) and bactericidal (0.30 mg/L) activity as compared with the reference drug, isoniazide (0.03 mg/L & 0.05 mg/L).

Biography:

Vaishali is a professor in Bharat Institute of Technology in India

Abstract:

Purpose: The HCV NS5B RNA-dependent RNA polymerase (RdRp) is a central enzyme in the replication of the viral genome and has since become a target of choice for screening and design of small molecule inhibitors for viral replication interference. Experimental description: A series of 4-pyridyl-1H-benzimidazole-4-(N-R1-carboxamide) derivatives was synthesised using two step reaction and NS5B RNA dependent RNA polymerase inhibition assay was used for in vitro evaluation. For insilico screening, the multiple regression analysis based QSAR model and molecular docking studies (FlexX) were used. Results: From in house compound library screening using NS5B polymerase enzymatic assay, we identified some benzimidazole derivatives. The activities were predicted using the QSAR generated models. Along with QSAR predictions, molecular docking studies were used to evaluate binding of these series of compounds at allosteric pocket (AP-1) of NS5B polymerase.

Conclusions: The QSAR and molecular docking directed study explains effects of substituents at position-2 and -4 of benzimidazole nucleus for HCV NS5B polymerase inhibition. In vitro preliminary evaluation results in identification of three compounds (4c, 4e, 4f) as promising NS5B inhibitor leads. Docking analysis of NS5B polymerase (AP-1) provided insight for the rational design of novel HCV inhibitors.

Biography:

Prasad V. Bharatam is a researcher in National Institute of Pharmaceutical Education and Research, India

Abstract:

The electronic structure of drugs provides several clues. The quantum chemical analysis of metformin (anti-diabetic),1,2cycloguanyl (anti-malarial),3,4 ebrotidine, famotidine (proton pump inhibitors),5,6 etc. in their protonated state were extensively studied.These provided clues regarding the electronic distribution and localization within these molecules. Further molecular docking, pharmacophore mapping and virtual screening methods were employed to design new guanylthiourea (GTU) derivatives as anti-malarial agents.7 Synthesis and biochemical evaluation of these species lead to the identification of these species as potential anti-malarial agents.8The details will be discussed in this presentation.

Biography:

Regents Professor Victor J. Hruby received his Ph.D. from Cornell University and did his Postdoctoral Studies at Cornell University Medical Center with Nobel Laureate Vincent du Vigneaud. Currently, he is a Regents Professor at the University of Arizona with appointments in four other departments and programs. He has over 1,200 publications, serves on the editorial boards of numerous journals, and has been a member of several NIH Study Sections. Dr. Hruby’s major research interests are in the chemical biology, conformation-bioactivity relationships, drug design, molecular mechanisms of information transduction of peptide hormones and neurotransmitters and their ligands that modulate health and disease. He has won numerous awards for his accomplishments including most recently the ACS Ralph F. Hirschmann Award, the ACS Arthur C. Cope Scholar Award, and the APS Murray Goodman Award.

Abstract:

Proopiomelanocortin (POMC) is a primordial animal gene that produces many of the key hormones and neurotransmitters critical for survival and reproduction. It also is involved in many of our most common degenerative diseases. It produces several hormones and neurotransmitters, including α-MSH, β-MSH, γ-MSH, ACTH, β-endorphin, β-lipotropin, etc. that target 5 melanocortin receptors (MC1R, MC2R, MC3R, MC4R and MC5R) as well as 3 opioid receptors and others. In the case of the melanocortin receptors, MC1R, MC3R, MC4R and MC5R, α-MSH (or δ-MSH) is the primary hormone/neurotransmitter and a common pharmacophore –His-Phe-Arg-Trp- is involved in agonist activation of the 4 receptors. This raises difficult problems in ligand design of agonists and antagonists for these 4 receptors which are involved in many diseases, including pigmentary diseases, feeding behavior diseases, sexual dysfunction, melanoma cancer, heart disease and many others. We have obtained highly potent and selective agonists and antagonists for the receptors that are stable and bioavailable. This required a combination of conformational and topographical considerations in peptide and peptidomimetic design. Several examples of successful applications of these considerations will be presented. Supported in part by grants from the U.S. Public HealthService, the NationalInstitutes of Health, NIDDK and GM.

Biography:

Dr. Yanli Wang obtained herPhD in computational biology in 1995from Peking University, China and completed postdoctoral studies from the National Institute of Cancer and National Center for Biotechnology Information (NCBI) during 1995-1998. She is currently the lead scientist of NCBI, primarily responsible for managing the PubChem BioAssay resource. She has published more than 40 papers in reputed journals.

Abstract:

The PubChem BioAssay database, created in 2004 by National Center for Biotechnology Information (NCBI) at NIH, serves as a public repository of bioactivity data for drugs, chemical probes, small molecules, and screening results for RNAi reagents. The database currently contains over 1,000,000 bioassay protocols and more than 200 millions of bioactivity outcomes for thousands of protein and gene targets and nearly three million substances. Information in PubChem can be freely accessed and downloaded using the NCBI information retrieval system Entrezat http://www.ncbi.nlm.nih.gov/pcassay/and a suite of services provided by PubChem at http://pubchem.ncbi.nlm.nih.gov. This presentation will describe PubChem utilities. In addition, arecent bibliometric analysis on applications of the PubChem resource by the community will also be described, which indicates that PubChem has been utilized by a broad range of research fields in the past ten years, and is becoming an important information resource for a number of research fields such medicinal chemistry, drug discovery, chemical biology and cheminformatics In particularly, the analysis shows an increasing trend in supporting wet laboratory research towards lead development and drug discovery using the bioassay data. PubChem welcomes feedback on the usability of the information platform and welcomes contributions from the community by sharing data. Chemical structures and assay results can be deposited via the PubChem submission system at: http://pubchem.ncbi.nlm.nih.gov/upload

Biography:

Maia Merlani has completed her PhD at the age of 27 years from Tbilisi State University. She is Senior Research Scientist at Tblisi State Medical University and at the same time holds a position of assistent professor at the King Tamar University at the patriarchate of Georgia. Her field of interest is chemistry of natural compounds. She has published more than 45 papers in reputed journals. She was granted Georgian President scholarship for young scientists (1997), NATO scholarship (2002) and Matstumae International foundation scholarship (2013).

Abstract:

From ancient times extracts, teas and pulps obtained from various comfrey species (Symphytum L., family Boraginaceae) and amongst them Caucasian ones (Symphytum asperum Lepech. and S.caucasicum Bieb. widespread in Georgia) are known in folk medicine as powerful wound healing and anti-inflammatory remedies. It was established that all aforementioned plants contain high molecular constituents namely a caffeic acid derived polyether - poly[3-(3,4-dihydroxyphenyl)glyceric acid] (PDPGA). Some of the plants medicinal effects, like its wound healing and anti-inflammatory properties, could be attributed to this polymer. Moreover, the polymer showed antioxidant, immunomodulatory and antitumor activity. Interestingly, this polymer is a first representative of a previously unknown class of natural occurring biopolymers: phenolic polyethers. Recently racemic and pure enantiomeric forms of PDPGA monomer - 3-(3,4-dihydroxyphenyl)-glyceric acid were synthesized as well as a methylated analogue of PDPGA -poly(MCDMPO). Comparative investigation of antioxidant properties of natural polymer and its monomer revealed that the latter appeared 40 fold active than polymer in both DPPH and chemiluminescence assays.

Biography:

Anna K H Hirsch read Natural Sciences at the University of Cambridge and spent her third year at the Massachusetts Institute of Technology. Her Master’s project focused on the double conjugate addition of dithiols to propargylic carbonyls under the supervision of Prof. S. V. Ley. She received her PhD in 2008 from the ETH Zurich working on the design and synthesis of the first inhibitors for the kinase IspE under the supervision of Prof. F. Diederich. Subsequently, she joined the group of Prof. Jean-Marie Lehn at ISIS (Strasbourg). Her research interests focus on rational approaches to drug design.

Abstract:

Energy coupling factor (ECF) transporters are a class of ATP-binding cassette (ABC) transporters that mediate the uptake of vitamins in prokaryotes. They consist of an energizing module and a substrate-binding protein (S-component). Different S components can interact with the same energizing module.1.ThiT is the thiamine-specific S-component.2. Based on the cocrystal structure of ThiT-thiamine (1).3 we have designed and synthesized thiamine analogues to identify which residues are the key for substrate binding and to elucidate the mechanism of transport.

Biography:

Ling Qiu is a researcher in Jiangsu Institute of Nuclear Medicine, China

Abstract:

Around the turn of the last century, Meyer and Overton demonstrated the correlation of olive oil solubility with anesthetic potency over a range of agents. Their original theory of anesthetic action proposed that since the largest source of cellular lipid components belonged to the cell membrane, anesthetics must therefore act by dissolving in and perturbing the nature of nerve cell membranes so as to produce the state of general anesthesia. However, since that time much protein mutational data as well as gross exceptions to this correlation have been found which not only imply a necessary hydrophilic component to anesthetic action, but also further demonstrate an ion channel protein mechanism of action, the nature of which is yet to be elucidated at an atomic level. While our previous work on the anesthetic-protein interactions has demonstrated the polarization of otherwise hydrophobic agents within a bound protein environment, it was limited by the rudimentary computational software and hardware of the time, as well as the limited availability of anesthetic-protein crystal coordinates. The work presented here now demonstrates, in a more rigorous manner, how quantum mechanics combined with molecular mechanics can reveal the true nature of interactions between the general anesthetics and the pentameric ligand-gated ion channels (pLGICs) across several complexes of the bacterial homologue from Gloeobacter violaceus (GLIC) with different anesthetics. Methods: All calculations were performed using the Discovery Studio 4.1 software suite and the ONIOM method implemented in the Gaussview5.0 and Gaussian09 programs. The coordinate files (PDB) for the complexes of pentameric ligand-gated ion channel GLIC (pH-gated bacterial homologue from Gloeobacter violaceus) with anesthetics desflurane (3P4W), propofol (3P50), bromoform (4HFH) and ketamine (4F8H) were obtained from the RCSB. These PDB files were prepared by adding hydrogens, setting AMBER force field parameters and optimizing the hydrogen geometries. An inner protein cavity within 10 angstroms of the anesthetic was carved out for each complex within which three ONIOM layers were defined as follows: a high layer involving the anesthetic ligand alone where density functional method could be applied using the hybrid meta exchange-correlation functional M06-2X with the 6-31+G* basis set; a middle layer involving residues within 4 angstroms of the ligand where PM6 semi-empirical quantum mechanics could be employed; and a lower level layer from 4 angstroms to 10 angstroms where the AMBER molecular mechanics forcefield could be implemented. The hydrogens and the anesthetic ligand then underwent geometry optimization while the protein backbone remained fixed. The root-mean-square deviation (rmsd) between the optimized structure and the crystal structure is applied as a criterion to evaluate any distortion of the ligand binding modes. Analyses of interaction energies, binding features, charge distributions and electrostatic potential surfaces were then performed for bound and unbound states of the ligand. Results: As in our previous work, three-layer ONIOM calculations continued to reveal that except for the anesthetic propofol within GLIC, other anesthetics’ binding sites within the GLIC are amphiphilic, not just hydrophobic. Anesthetic-GLIC interactions include several van der Waals interactions and other weak polar interactions. However, our current work allows the elucidation of additional results. Geometry optimization of the ligand within the binding site produced minimal alteration in position of the ligand to that of the original crystal structure, but did reveal presence of hydrogen bonding and halogen bonding between anesthetic and protein moieties. The steric effects within the binding sites play a dominant role in the anesthetic-GLIC interactions over the polarization effects, and the steric effects cause a significant asymmetry in the otherwise symmetric atomic charge distributions of the symmetric ligands in vacuo. Conclusions: The rigorous three-layer ONIOM calculations combined higher level quantum mechanics with lower level quantum mechanics and molecular mechanics, which not only reveal the amphiphilic nature of anesthetic-GLIC interactions except for the propofol, but also show the domination of steric effect within the binding site as well as the existence of hydrogen bonding and halogen bonding potential.

Biography:

Seema Dhail is currently working as split-site Ph.D. research scholar in Bar-Ilan University, Israel. The topic of her research studies is on “Quantum mechanical studies of bioactive molecules invoking QSAR”. She did her Pre-Doctorate (M.Phil) in Life sciences (specialization in Biotechnology) from Rajasthan University, India. She has 15 research papers published in International Journals of high repute and one patent has been filed on novel isolated bacterial strains from Arabian Sea. She got Israel scholarship for split-site Ph.D programme and nominated as split-site research scholar from India for Commonwealth scholarship for UK. She Cyclin A/CDK2 Cyclin B/CDK1 Cyclin D/CDK2 Cyclin E/CDK2 QSAR Phosphorylation of target Protein binding CDK S phase G2 phase M phase G1 phase Cyclin Target Protein Target Protein binding CDK/Cyclin complex Descriptor Calculation Model Building Cell Cycle also got an opportunity to visit Turkey in an International Conference on Environmental Science and Technology as a scientific member, where she presented a paper and also chaired a session.

Abstract:

Quantitative Structure Activity Relationship (QSAR) models correlate a specific activity for a set of compounds with their structure-derived descriptors by means of a mathematical model. Such models have been widely applied in many fields including chemistry, biology, and environmental sciences. The role of QSAR models in the identification of new compounds and in their subsequent optimization has been constantly growing and is now recognized by many practitioners of computer aided drug design methodologies. QSAR models highly depend on the molecular descriptors. Many types of descriptors with varying degrees of complexity have been described in the literature. These could be classified into 1-dimentional (1D), 2D and 3D or into "classical" and quantum mechanics (QM)-based. A rigorous comparison between the performances of classical and QM-based descriptors is currently lacking. Here we take the first step towards performing such a comparison by deriving QSAR models for a series of CDK/Cyclin inhibitors, important as potential anti-cancer therapeutics. We focused on a set of 40 ligands with known crystal structures (available in the PDB) and IC50 values. Reliance on crystal structures which are assumed to represent the bioactive conformations of these ligands allows for the accurate calculation of conformation-dependent 3D descriptors. Seven sets of molecular descriptors were calculated including 1D, 2D, 3D and QM-based and used to derive QSAR models by means of a Genetic Programming (GP) approach. Overall models with good prediction statistics were obtained highlighting the importance of specific descriptors

Biography:

Keiko Ikemoto, MD,PhD,graduated Shiga University of Medical Science in 1985, specialized in Psychiatry and Neuroscience. She studied monoamine neuronal system and sleep as Boursiere du GouvernementFrancais in the Department of Experimental Medicine, Claude Bernard University (1995-1996). She continued research in Department of Anatomy, Fujita Health University,Hanamaki National Hospital, Fukushima Medical University, School of Medicine, Shiga University of Medical Science, and Iwaki Kyoritsu General Hospital, in Japan. She organized the 1st Symposium for Brain Bank, in Fukushima in 2006. Now she chairs the Department of Psychiatry, Iwaki Kyoritsu General Hospital, Japan.

Abstract:

Recent pharmacological studies have shown the importance of trace amine-associated receptor, type 1(TAAR1), a subtype of trace amine receptors, as a prospective target receptor for novel neuroleptics. Endogenous ligand producing neuron of TAAR1 is the D-neuron, i.e., trace amine neuron, defined as “the aromatic L-amino acid decarboxylase neuron, neither contains dopamine (DA) nor serotonin”. We found significant decrease of D-neurons (trace amine neurons) in the nucleus accumbens (Acc) of autopsy brains of patients with schizophrenia. Animal model studies have shown that reduced stimulation of TAAR1 on DA neurons in the midbrain ventral tegmental area (VTA) increased firing frequency of VTA DA neurons. Thus, D-neuron reduction and consequent trace aminedecrease, causing TAAR1 stimulation reduction on terminals of midbrain VTA DA neurons has been shown as the molecular basis of mesolimbic DA hyperactivity of schizophrenia. D-neuron decrease in Acc of postmortem brains is supposed be due to neural stem cell (NSC) dysfunction in the subventricular zone of lateral ventricle (cf. NSC dysfuction hypothesis of schizophrenia).The new “trace amine hypothesis” (“D-cell hypothesis”), of schizophrenia in which D-neuron and TAAR1 is involved, is in agreement with recent reports showing effectiveness of TAAR1 ligands for schizophrenia model animals. This hypothesis links DA hypothesis of schizophrenia with NSC dysfunction hypothesis. D-neuron reduction in the Acc, an anatomical area known for an antipsychotic acting site, would let us assume TAAR1 ligand searching study being pivotal in novel neuroleptics discovery.

Biography:

Byran Gowramma is a professor in JSS College of Pharmacy, India

Abstract:

The oxidative cyclization of thiosemicarbazone (I) was carried out using ferric chloride as an oxidative agent to get 2- amino- 5- styryl -1, 3, 4-thiadiazole (II). 2- amino- 5- styryl -1, 3, 4-thiadiazole (II) reacted with aromatic aldehydes in methanol to give the new product N- (4-sustituted)- 5- styryl- 1, 3, 4-thiadiazol-2-amine (IIIa-h). Compound (IIIa-h) reacted with chloroacetyl chloride in triethylamine to give 2-azetidinone derivatives bearing 1, 3, 4-thiadiazole nucleus (IVa-h). Compound (IIIa-h) on cyclo condensation with mercaptoacetic acid leads to the formation with 4-thiazolidinone derivatives bearing 1, 3, 4-thiadiazole ring (Va-h). Synthesis of all titled compounds were confirmed by melting point, IR, 1H-NMR and Mass spectrum and evaluated for their anti-inflammatory activity. Out of the synthesized compound IVa and IVb were capable of showing very good anti-inflammatory activity almost on compared with that of the standard ibuprofen, followed by IVc while the rest of compounds were found to be mild in their potency.

Biography:

Bharathkumar Inturi is final year PhD studet at Dept. of Pharamceutical Chemistry, JSS University, Mysuru. He has published more than 10 papers in reputed journals

Abstract:

Mycobacterium tuberculosis responsible for nearly two million deaths each year[1], the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug- and extensively drug-resistant strains of mtb confounds control efforts, and new drugs with novel molecular targeting approaches are desperately needed. The current study describes the use of protein−ligand-derived pharmacophore model as a tool to identify the novel Mtb InhA inhibitors. The pharmacophore model was generated considering the ligand, hydrogen bonding interactions and active site of targeted protein. We have developed a three feature pharmacophore model consisting donor, hydrophobic and aromatic features by considering the co-crystallized ligand of InhA(Fig-1A) (PDB:3FNG)[2] and also hydrogen bond interactions(Fig-1B) and active site of the co- crystallized ligand(Fig-1C).This model was used to search the database of 200,000 molecules. Best 5000 hits was considered for molecular docking approach, from the docking results, top hits were further considered for the molecular dynamic study to find the stability of protein ligand interaction stability. Based on dynamic results best 5 molecules were synthesized and the evaluation is under progress against mtb H37Rv.

Biography:

Divyanshu Sharma is a researcher in Rajiv Academy For Pharmacy, India

Abstract:

Various heteroannulated carbazole derivatives have drawn much attention because of their natural occurrence and the broad spectrum of biological activity associated with these compounds. In view of broad biological activity of carbazole derivatives, we planned to synthesize new carbazole derivatives by incorporating new pharmacophores such as oxadiazole, thiadiazole, azetidinone and thiazolidinone at the 9th position of carbazole nucleus with the hope to get better pharmacologically active drugs.In the same direction a one pot, comparative method was developed to synthesize a series of 5-((9H-carbazol-9-yl) methyl)-N-((substituted phenyl)-(piperazin-1-yl)methyl)-1,3,4-oxadiazol-2-aminederivatives as N-Mannich’s bases. Carbazole was taken as a starting material to react with ethylchloroacetate to produce Ethyl-N9-carbazolyl acetate(1). Compound 1 was treated withsemicarbazide to give (N9-carbazolyl acetyl)semicarbazide(2) which was then reacted with concentrated sulfuric acid to produce 5-((9H-carbazol-9-yl)methyl)-1,3,4-oxadiazol-2-amine(3). To this different aromatic aldehydes were added in the presence of piperazine to produce the corresponding 5-((9H-carbazol-9-yl)methyl)-N-((substituted phenyl)-(piperazin-1-yl)methyl)-1,3,4-oxadiazol-2-amine(4 a-j).All the synthesized compounds were checked for purity by melting point and TLC. All the synthesized compounds were characterized by FTIR, 1H NMR, MASS spectral studies and elemental analysis. Finally all the synthesized derivatives will be evaluated for their antibacterial, anticancer and anticonvulsant activities.

Biography:

Dr. Carsten Detering obtained his PhD in Physical Chemistry from the Freie Universitaet Berlin in Germany in 2001. He did his Post Doc at the University of Washington in Seattle where he worked on the application of docking software for nucleic acid drug targets and rational design of new inhibitors for a malaria project. In 2005 he came to BioSolveIT in Germany as an Application Scientist first, later filling the position of Senior Key Account Manager and Executive VP of Sales, North America, before moving back to Seattle as CEO of BioSolveIT Inc, the north American subsidiary of BioSolveIT.

Abstract:

Predicting binding affinity (aka scoring a protein-ligand complex) has been heavily criticized as long as it exists. Sometimes it works on this target, sometimes on another target, but there are few, if any that work consistently well on all targets. One possible explanation and certainly a drawback could be that existing ways of predicting binding affinity (scoring functions) look at favorable interactions, neglecting those interactions that are unmet, which consequently brings into a virtual screening a lot of false positives. BioSolveIT's scoring function Hyde takes on these challenges and is radically different. It is based on pure physico-chemical principles and takes into account hydrogen bonding and the hydrophobic effect. It penalizes missing interactions, wherever a hydrogen bond is not established or a group is misplaced in the active site. This effectively rules out most false positives. There are cases, however where there is hardly coincidence between the experimental and the calculated affinity. Does this mean Hyde does not work as reliably as we expect? We will look at some examples and check who we should trust: our crystal structures or the Hyde scoring function.

Biography:

Vijay Kumar Singh has completed his post graduation from Bundelkhand University, Jhansi, India. Presently he is working as ‘Lecturer’ in the Institute of Pharmacy, Bundelkhand University, Jhansi and submitted his doctoral research at Monad University, Hapur, India. He has 4 International and 8 National research papers to his credit and the writer of one book entitled “Synthesis and Antimicrobial Activity of Benzotriazole Derivatives” (Concept, Synthesis and Spectral analysis), Lambert Academic Publishing, Germany ISBN: 978-3-8454-3275-5. He has been serving as an editorial board member of IJPSR (International Journal of Pharmaceutical Sciences and Research ISSN: 0975-8232) and IJRDPL (International Journal of Research and Development in Pharmacy and Life Sciences ISSN: 2278-0238)

Abstract:

Benzotriazole, Thiadiazole and Imidazole showed diversified pharmacological activity. In view of potential biological activities of Benzotriazole, Thiadiazole and Imidazole, it was considered worthwhile to synthesize some 3, 5-(di-substituted)-5-[(N-Benzotriazolomethyl) -1, 3, 4-Thiadiazolyl] - 1H-imidazole -2-thione and screen out some derivatives which show marked anticonvulsant activity. A new scheme of synthesis is designed to attach benzotriazole, thiadiazole and imidazole nuclei to form a single molecular framework (X) starting from Benzotriazole. Out of 20 synthesized derivatives three molecules show excellent anticonvulsant property. The experimental procedure has already been approved by IAEC (Institutional Animal Ethical Committee) as per the guidelines given by CPCSEA (Council for the purpose of control and supervision on experimental animals).

Biography:

Yong-Hwan Lee has completed his PhD majoring in structural biology and protein chemistry from State University of New York, Stony Brook, and postdoctoral studies from University of Minnesota School of Medicine. He is an Adssociate Professor, Department of Biological Sciences, Lousiana State University and has successfuly developed PFKFB3 inhibitors as cancer therapeutics. He has published more than 30 papers in reputed journals and has been serving as an ad-hoc reviewer of NIH and reputed journals.

Abstract:

Epigenetic modification of histone is an important mechanism for control of development and maintenance of tissue-specific gene expressions. Anormaly in epigenetic modifications causes an altered pattern of gene expressions and often leads to malignant transformations. Impaired epigenetic control has been considered as one of the key features of cancer and, thus, artificial control of epigenetic modification is an emerging strategy of anticancer therapy. G9 methyl transferase, one of the most prominent histone methylation enzyme, catalyzes transfer of a methyl group from SAM to Lys9 of Histone3 (H3K9), resulting in mono- (me1), di- (me2), and tri-methylated (me3) H3K9. Methylation of H3K9 is one of the repressive histone marks that silence tumor suppressor genes and G9a has been observed to be up-regulated in various cancers, suggesting that G9a is a putative oncogenic protein. Supporting this speculation, G9a knock-down using shRNA resulted in decreases in global H3K9 methylation levels and led to ultimate autophagic or apoptotic cell death. Several G9a inhibitors have been developed as potential cancer therapeutics but with severe cellular toxicity, probably because of off-targeting of other SAM-binding proteins. For the enhanced application to practical cancer therapy, we developed new inhibitors, which are highly selective for H3K9me3 methylation and, thereby, significantly less cytotoxic, via the virtual screening of 18 million compounds and the subsequent biochemical activity assay. Finally, eight candidate compounds with IC50s in a low micromolar range are identified and being optimized for development of new G9a inhibitors with drug potentials.

Biography:

Andreia Valente completed her PhD in 2010 from the Université de Lille I (France) on the field of Polymerization Catalysis. Then, she joined the Organometallic Group at Faculty of Sciences, University of Lisbon (Portugal) where she got a first post-doc position in synthesis of organometallic compounds for nonlinear optic applications, followed by a second post-doc in the field of medicinal inorganic chemistry. She is presently a researcher (academic) at the same Institution, directing now her efforts to the synthesis of new polymer-metal complexes as targeted drug-delivery systems in view to cancer therapy

Abstract:

A new family of multifunctional polymer-ruthenium conjugatesfor targeted delivery of chemotherapeutic agents has been synthesized and tested as anticancer agents. These drugs might provide potential tools to surmount many of the current limitations in conventional chemotherapy, including undesirable biodistribution, cancer cell drug resistance and severe systemic side effects. Our approach constitutes an innovation relatively to other high molecular drugs reported in the literature mainly because an exact control of the amount of our cytotoxic drug in the polymeric chain is achievable due to our fine tune functionalization of the polymers (other approaches use a variable percentage of metal per quantity of drug). Studies of drug speciation in blood, cytotoxicity, apoptosis, autophagy, proliferation, in vitro drug internalization and release studies and ultrastructure analysis of cells led to the identification of a lead compound that has been subjected to in vivo studies in nude mice. In vivo studies comprise pharmacokinetics by controlling the amount of metal (Ru) in organs, tumor, blood and urine of mice. Hematological and biochemical parameters of the animals were evaluated as well as tumor regression and metastasis inhibition.

Biography:

Alessandra Nurisso has completed herPhD in structural glycobiologyat the age of 27 years from Grenoble University (France). In 2010, she joined thepharmacochemistry laboratory of the School of Pharmaceutical Sciences of the University of Geneva (Switzerland) as a post-doctoral researcher in computer-aided drug design. Dr. Nurissois currently lecturer in medicinal chemistry at the University of Geneva, at the University of Grenoble, and, since 2013, chair of excellence of the University of Geneva (Switzerland).Her current research focuses on in silico driven strategies for the design of novel molecules targeting epigenetic enzymes.

Abstract:

Sirtuins (SIRTs) are a family of enzymes able to catalyze the deacetylation of the N-acetyl lysines of both histone and non-histone substrates. Inhibition of their catalytic activity was recently reported in the literature as being beneficial in aging-related diseases such as cancer and neurodegeneration. By combining a structure-based virtual screening approach of highly diverse molecular libraries with fluorescence-based deacetylation assays, we identified new scaffolds for the inhibition of SIRT catalytic activity. For these compounds, all active in the low µM range, both mechanisms of inhibition and binding modes were elucidated. Moreover, physiochemical properties for passive adsorption and cytotoxicity data were investigated in vitro. We then demonstrated the capacity of these SIRT inhibitors to strongly repress angiogenesis in cells, in a Fox O-dependent fashion. Our study provided promising compounds able to target SIRTs that could be useful for both research and therapeutic purposes.

Biography:

Dr. Hamed I. Ali got his PhD in medicinal chemistry from Okayama University, Japan. Currently, he is an Assistant Professor at Texas A&M Rangel College of Pharmacy. He has devoted his research career to design, synthesize, and biological screening of antitumor agents against different tumor cell lines. Recently, his ongoing research focuses on SAR and synthesis with optimization of chemical functionalities of Iindole-2-carboxamides to improve their allostery for the CB1as potent AM for the CB1 cannabinoid receptors, and virtual screening for hits to get lead compounds.

Abstract:

In attempting to improve the efficacy of 5-deazaflavin derivatives as antitumor agents, novel 2-(N-substituted amino, hydrazino and heterocyclic amino), 2,2'-(piperazine-1,4-diyl)-bis(10-alkyl)-, and 2[(E)-2-(substituted) benzylidene hydrazino] derivatives were designed. These compounds were prepared by nucleophilic substitution of C2-methylthio group. The 10-aryl-2-thioxo- and 2-(substituted amino)-10-aryl derivatives were prepared by condensation reaction of 6-anilino-2-thioxopyrimidin-4(1H)-one analogs with o-bromobenzaldehyde and 2-(substituted amino)-10-aryl analogs with different amines and hydrazine, respectively. Many compounds revealed promising IC50 of nanomolar range against MCF-7 and Hela tumor cell lines. The potential antiproliferative activity against MCF-7 cells was detected for 5-deazflavin analogs with the following structural features: 2-(o-bromo-, o-chloro-, or unsubstituted) benzylidene hydrazine, 2-benzylamine, 2-morpholine, 2-hydrazine, 10-small alkyl, and the 2,2'-dimeric structure linked by piprazine ring. The selectivity towards MCF-7 over HeLa cells was revealed by 2-hydrazino-10-ethyl, 2-morpholino-10-ethyl, 2-(2-chlorobenzylidene) hydrazino]-10-methyl, and 2-(2-bromobenzylidene) hydrazino]-10-ethyl compounds. Whereas, selectivity towards HeLa cells was shown for 2-thioxo-10-(o-tolyl) and 2-benzylamino-10-(p-chlorophenyl) analogs. In this study, we got derivatives with IC50 of nanomolar range more than our earlier reported studies of micromolar ranges. Over the above, the molecular docking of many compounds showed good affinities into c-kit PTK domain with low binding free energies. Substitution with phenyl rings at the 2- or 10-position results in better fitting into PTK and enhancing their antiproliferative potency. Many of these 5-deazflavins exhibited a good correlation between their IC50 and their AutoDock binding free energies (DGb) and inhibitions (Ki). Therefore, they represent new classes of promising candidates as potential antitumor agents and PTK inhibitors.

Biography:

M Helena Garcia is Associate Professor with “Habilitation” at University of Lisbon.Her scientific areas of research have been mainly centered in synthesis of organometallic compounds in view to potential applications with benefit to the society.She has authored over eighty publications and several book chapters. She has been leader of several national and European funded scientific research projects and isMember of the “Division of Organometallic Chemistry” of European Association for Chemical and Molecular Sciences, as delegate of Portuguese Chemical Society, since 1992. She is Coordinator of the International Office at Faculty of Sciences, University of Lisbon.

Abstract:

In the recent years our group has been involved in the synthesis of new ruthenium organometallic complexes which cytotoxicity against several cancer cell lines was found, in most of the cases, better than that of cisplatin. In particular important IC50 values were found for the triple negative breast cancer (TNBC) and prostate cancer cells when treated with compounds which structures are based in the fragment “Ru(h5-C5H5)” with two different appended molecules.[1-2] Thus, three compounds of the panel were selected having in mind to understand any possible correlation between chemical structure and in vitro / in vivo activity. The main structural changes were the replacement of N,N by a N,O heteroaromatic ligand or inclusion of a sulphonate group in the phosphane ligand in order to increase water solubility. Although our in vitro studies such as cellular distribution, morphological alterations caused by drugs, binding to serum proteins, between others, revealed very similar responses for our selected drugs, their behaviour in vivo was completely different. While the therapeutic effect of one of these compounds evaluated in an orthotropic TNBC mouse model demonstrated the capacity to suppress tumour growth, not presenting the severe side-effects of other non-targeted chemotherapeutic agents, this was not the case of the other two compounds tested for prostate cancer. In fact, severe side effects were observed in the animals for one of the drugs while the other drug was excreted without exerting any effect neither in the animal nor in the tumour.

Biography:

Zechariah Marting has just completed his PhD in the Faculty of Pharmacy of The University of Sydney. He is a lecturer in the Faculty of Pharmaceutical Sciences of the University of Jos, Plateau State, Nigeria. He has served in different capacities before moving to Australia to do PhD Program in Drug design, evaluation, and synthesis. He is credited with one publication.

Abstract:

The chemotherapy of human cancer in modern times still faces enormous challenges for its complexity, resistance, and absence of an integral molecular operation that targets any known group of the malady [1, 2] at once. EGFR (ErbB1/HER1) and its subfamily members ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4) exhibit the most crosstalk of signalling among themselves and other paths [3] and are crucial to regulating cell proliferation, apoptosis, migration, differentiation and survival, following activation and induced conformational change by a cognate ligand such as EGF, which then undergoes an oligomerization process in the oligomerization region. In aberrancy, EGFR, as an archetypal of the subfamily most studied is a most featured receptor in several solid carcinomas such as breast and NSCLC, occurring as homo- or hetero-oligomers (dimer or tetramer) [4-6]. Fewer small molecules have been developed to target the region that influences significantly the downstream signal transduction, for instance, via posttranslational modification of proteins that causes auto-trans-phosphorylation of tyrosine residues the downstream signal cascades depend on. LigPrep (version 3.0, 2014-4) and Epik (version 3.0, 2014-4) on Maestro (Version 9.8, 2014) as the graphical use interface of the Schrodinger Suite (Schrodinger Inc., NY, USA), were utilized to design lead candidates 3-(furan-2-yl)-4-(8-hydroxyquinolin-2-yl)-1,4,6,7-tetrahydro-5Hpyrazolo[ 3,4-c]pyridin-5-one (IC50 = 0.13nM); 3,3,3-trifluoro-2-hydroxy-N-((2-(4 methylpiperazin-1-yl)pyridin-3-yl)methyl)propanamide (IC50 = 33.42nM); 2-((2-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methyl)quinolin-8-ol (IC50 = 3.05μM) and 5-(1-cyclopentylpyrrolidin-2-yl)-N-((3,5-dimethyl-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide (IC50 = 0.32μM) lead molecules that target the oligomerization region. Two novel compounds 2-hydroxy-N-(4-hydroxybenzyl)-2-(4-hydroxyphenyl) acetamide, had potent antioligomerization activity (IC50 = 0.63 μM) and N'1,N'2-dicyclopentylideneoxalohydrazide (not yet bio evaluated) were synthesized on optimization of lead candidates using Combiglide (version 3.5, 2014-4).

Biography:

Dr. Arafa has completed her PhD at the age of 28 years from Goergia State University and postdoctoral studies at the same University. She acquired her Associate Professrship in 2010. Currently Dr. Arafa is appointed as Associate Professor of Biomedical Sciences and Coordinator of the Drug Design and Discoveru Program in Zewail City of Science and Technology. Dr. Arafa has published more than 30 papers in reputed journals in the field of drug design and medicinal chemistry.

Abstract:

Naturally occuring flavonoids have elicited a proven role as capacity having agents for the management of cancer. Thus, this research deals with the design and synthesis of semisynthetic flavonoid scaffold based derivatives viz furochalcones (3a-e, 6a-d and 9a-d), furoflavones (10a-d, 11a-d, 12a-d, 18a&b), flavones (21a-d), furoaurones (13a,b, 14a-d and 15a-d) and 7-styrylfurochromones (22a-d and 25a-e). The novel compounds were evaluated for their antiproliferative activity against a panel of 60 cancer cell lines comprising 9 types of tumors. Ten compounds belonging to the major subgroups of flavonoids viz furochalcones (3a, 3d, 6b, 9a and 9b), furoflavones (12a and 12c), furoaurones (15d), styrylfurochromones (25b and 25e) showed very promising activity. These active compounds were also evaluated in vitro as kinase inhibitors against CDK2/cyclin E1, CDK4/cyclin D1 and GSK-3β and the best inhibition was displayed against GSK-3β with the allylfurochalcone derivative 9b exhibiting 80% decrease in GSK-3β catalytic activity. On the other hand, the styrylfurochromone 25e interestingly showed a 13% enhancement of GSK-3β catalytic power and a 12% reduction in CDK4/cyclinD1 activity. Finally, the in vivo anti-tumor activity of 25e was evaluated against breast cancer induced in mice. The results showed a profound anti-tumor effect of 25e that accompanies a significant increase and decrease in the levels of GSK-3β and cyclin D1, respectively.

Biography:

Conrad V. Simoben is a researcher in University of Buea, Cameroon

Abstract:

A recent survey of natural products (NPs) from African plants has shown that, medicinal plants from Africa possess anti-cancer like activities (ranging from “mild” to “very good”).1,2 The survey consisted in collecting data from published literature sources. These data included; plant sources, uses of plant material in traditional medicine, plant families, region of collection of plant material, isolated metabolites and type (e.g. flavonoid, terpenoid, etc.), measured biological activities of the isolated compounds and any comments on significance of isolated metabolites on the chemotaxonomic classification of the plant species. The collection was composed of ~400 input compounds, isolated from some plant species collected in Africa. An attempt to classify and identify plants from African flora, according to demonstrable differences and similarities in their bio-chemical compositions was done based on data published so far, by presenting trends towards the full description of the taxonomy of the studied families and species. A number of cheminformatics parameters were calculated to assess the “drug-like” or “lead-like” properties of the isolated NPs from African flora. For example, Lipinski’s “Rule of 5”3,4 and Oprea’s “Rule of 3.5”5-7 use simple molecular parameters like molecular weight (MW), lipophilicity parameters (log P), number of hydrogen bond acceptors (HBA), number of hydrogen bond donors (HBD), number of rotatable bonds (NRB) and two dimensional polar surface area (2D-PSA) to roughly determine the proportion of compounds within a library which can be developed into drugs or lead compounds respectively. At the end of this study, we had done a literature survey and collection of secondary metabolites data for NPs, which have been previously isolated or derived from African flora. A correlation between the anti-cancer activities of isolated compounds and the ethnobotanical uses of the plants were also established. The application of computer-based modeling for the search of lead compounds is a promising endeavour in drug discovery, since it often accelerates the process and cuts down costs.8 So we would be providing some pharmacophore models that have been generated and validated for use in virtual screening against some selected cancer targets.

Biography:

Anjala. W. Bulathge is a researcher in University of Peradeniya, Sri Lanka

Abstract:

pH sensitive drug delivery systems can achieve targeted drug delivery and systemic control release. The studies in this area have been increased in recent years and more attention has been devoted to develop new methods for the preparation of new drug delivery systems especially in cancer therapy. Among the metal based anti-cancer drugs, copper complexes have shown remarkable potential in cancer therapy. Therefore, the aim of this study is to synthesize a pH-sensitive calcium carbonate-encapsulated copper bis-(8-hydroxyquinoline) anti-cancer drug delivery system starting from naturally occurring dolomite. In this novel research, first, copper bis-(8-hydroxyquinoline) is synthesized using copper(II) chloride dihydrate and 8-hydroxyquinoline as the reactants. The drug was loaded to the preformed hollow structures of precipitated calcium carbonate (PCC) by physisorption method. Hollow structures of PCC were suspended in prepared solution of Copper bis-(8-hydroxyquinoline) dissolved in Dimethylformamide (DMF). It was moderately stirred for five days. PCC products were collected by centrifugation followed by washing with acetone to remove the DMF. The obtained product was characterized using XRD, XRF and FTIR studies. XRD and FTIR studies revealed that copper bis-(8-hydroxyqunoline) incorporated inside the CaCO3 hollow PCC product. The release of drug is monitored in vitro in the pH values of 2.0, 4.0, 6.0 and 8.0. According to results, within first four hours, the cumulative release shows 100% in pH 2 and pH 4. However, no release is observed in pH 8 for 120 hours. Therefore, it is a good indication that the encapsulated drug releases at the pH trigger point. pH differences can be found at the subcellular level, late endosomes and lysosomes have much lower pH, in the range 4.5–5.5 . Due to high rate of glycolysis, tumors exhibit pH value 5.7 while the pH value of normal tissue is 7.4. This pH gradient is very important in internalization of drugs. Therefore this has potential applications in effective cancer therapy.

Biography:

M. Thirumala Chary is a professor in JNTUH College of Engineering, India

Abstract:

Quinoxalines have been found to exhibit various biological activities such as antibacterial, antifungal, anti-tubercular, anxiolytic, anticancer, antioxidant, anti-inflammatory, anti-HIV, antihelmintic and anticonvulsant. The present study aims to synthesis, characterization and determination of antimicrobial susceptibility testing of various novel quinoxaline derivatives. The quinoxaline-benzohydrazides 6a-m was obtained by the condensation of quinoxaline-2-carboxaldehyde 4 with various benzohydrazides 5a-m in ethanol at reflux temperature. All the newly synthesized quinoxaline-benzohydrazide derivatives were characterized by 1H NMR, IR and mass analysis. The synthesized quinoxaline-benzohydrazides 6a-m was screened for antibacterial activity. Most of the compounds showed significant antibacterial activity.

Biography:

Jesus Garcia Gamez is medical student of Escuela Superior de Medicina at Instituto Politécnico Nacional. He is a junior researcher who has been working at Biochemistry Department since 2013 on different research lines such as asthma, Parkinson and obesity. His recent research is focused on drug design for cancer treatment

Abstract:

Cancer is an uncontrolled process of growth and dissemination that can appear ubiquitously. Genetic and epigenetic mutations in cancer cells elicit protection of tumor cells like overexpression of histone deacetylase (HDAC). HDAC inhibitors (HDACi) have shown that over acetylated state induce anticancer effects like apoptosis, cytostasis, differentiation and angiogenesis inhibition. HDAC8 is overexpressed in different types of cancer such as colon, breast, lung, pancreas, ovary, etc. Therefore, we modeled a serie of isoindoline-1,3-dione due to their homology with thalidomide's metabolites and also similar to HDACi previously reported just as sodium butirate, sodium valproate, phenylbutanoic acid, etc. Docking results showed our ligand DxD2-15 interacting with HDAC8 in the catalytic site with the amino acid residues Phe208, Phe152, His180, Met214, Asp178, Tyr306, Gly303 and Gly304 suggesting possible inhibitory effect. Antitumoral capacity of DxD2-15 was tested in different concentrations at 24 and 48 h on L5178-Y murine leukemia cells with MTT assay. Cellular viability decreased importantly after 24 and 48 h of culture. There was a significant decrease in cell viability caused by DxD2-15 at all times and concentrations of 1X10-4 M, 1X10-5 M and 1X10-6 M showing DxD2-15 as a potent antitumoral drug compared with control cells (P<0.05). With these important results we propose to perform more experiments on other cell lines such as HeLa, Vero and prostate cancer cells and also perform in vivo experiments in male Balb/C mice.

Biography:

Alicia Merlino completed his PhD in Medicinal Chemistry in 2010 at Facultad de Química, Universidad de la República, Uruguay. Since 2011 she works as Adjoin Professor at the Theoretical and Computational Chemistry Group in Facultad de Ciencias and has worked in CADD against different therapeutic targets in collaboration with several research groups. She has publishednumerous papers on this area in recognized journals. Since 2012 she has been responsible for the project “R&D of caspase-3 inhibitors as potential drugs against Alzheimer’s Disease”for which has received a grant last year. She is mentoring a pre-grade student and two Master students.

Abstract:

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide for which there is currently no cure. One of the main reasons that has prevented the development of an effective treatment for AD is that molecular factors that cause the disease have remained elusive. Recently caspase-3 has been proposed as a potential therapeutic target for treating AD. Caspases inhibition is not an easy task because they are involved in a variety of cellular processes. However, since caspase-3 is overexpressed in brains from AD patients its selective modulation by non-covalent and selective inhibitors becomes an interesting strategy in the search of potential drugs against this neuropathology. With this in mind, our research group has been working in the capacity of a series of nitrones to inhibit caspase-3 mediated apoptosis in mouse hippocampal (HT22) cells. Moreover, the mechanism of inhibition of caspase-3 by nitrones was evaluated by means of molecular docking and molecular dynamics (MD) simulations. Most of the evaluated nitrones are able to inhibit apoptosis in neuronal HT22 cells. According to docking and MD results these molecules would be able to act as caspase-3 inhibitors by binding into a region close to the substrate binding site and causing important allosteric changes at the catalytic site. Interestingly, nitrones interact with residues that are not conserved in other caspases and therefore they could be promising selective inhibitors of caspase-3. Enzymatic assays in order to test the capacity of these nitrones to selectively inhibit caspase-3 are currently underway.

Biography:

Erik Andrade-Jorge is a Doctorate student in the Department of Biochemistry atInstitutoPolitecnicoNacional. He is a chemist-pharmaceutical-biologist and has a Master degree in Pharmacology and is currently in the fifth semester of the Doctorate in research in medicine. Currently, he has three different research lines one of these is cancer cell proliferation, another one is in Parkinson’s disease and the third one is in obesity. He has been focused on the rational drug design based on the molecular mechanisms of different pathologies.

Abstract:

Parkinson's disease is a chronic neurodegenerative disorder that eventually leads to progressive disability, this occurs as a result of the destruction of dopaminergic neurons of the substantianigra. The purpose of the current treatment is to cover the deficiency of dopamine, but due to the high degree of homology between the D2 and D3 receptor it has been difficult to obtain selective compounds for one of the two receptors. Therefore, the aim of the present study was to design and evaluate a series of 2,3-dihydro-1H-isoindoline to test their selectivity for the dopamine D2 receptor. Docking results showed that the ligands that have more affinity for the D2Hu receptor are molecules MD2m13-13S, MD2f13-6S and MD2g13-7S with a ∆G of -7.67, -7.18 and -6.99 Kcal/mol respectively and interact with 12 amino acid residues in the orthosteric site that are reported as important for recognition. In the study of the molecular and toxicological properties, the isoindolines showed that possess favorable characteristics as potential drugs. Taking into account the in silico results, it was carried out the synthesis of the molecule MD2a13-1 and its structure was confirmed by IR, 1H and 13C NMR and mass spectroscopy. The in vivo evaluation showed that this compound has effect on motor activity of male C57BL/6 mice in the MPTP model. These results allow us to try other candidates who might possess the same properties and also perform binding studies that can give us more evidence about the selectivity for the dopamine D2 receptor.

Biography:

Concepción González-Bello has obtained her PhD at the University of Santiago de Compostela (USC, Spain) in 1994. She did two Pre-Doctoral stays in the University of Gent (Belgium) with Professor Vandewalle and in the Scripps Research Institute (USA) with Professor Nicolaou. After a Postdoctoral stay in the University of Cambridge (UK) with Professor Abell, she joined USC as an Assistant Professor, was promoted to Associate Professor in 2003 and obtained the Spanish habilitation to Full Professor in 2011. She is Author of more than 65 papers and several book chapters. She is a Member of the ChemMedChem International Advisory Board.

Abstract:

According to the World Health Organization, antibiotic resistance is becoming a public health emergency of unknown proportions. Therefore, there is a great interest in the discovery of novel drugs and therapies to tackle antimicrobial resistance, in particular drugs that target unexplored essential processes for bacterial survival. For this purpose, a detailed knowledge of the catalytic mechanism, the binding determinants and the essential motion for catalytic turnover of selected enzymes involved in biosynthetic pathways or processes that do not have mammalian homologs, but are essential for bacterial survival, can be valuable for the rational design of these mimetics (inhibitors) that can be used as drugs. Our research group is studying the possible development of new antibiotics whose mode of action is based on the selective and effective inhibition of an essential enzyme in bacteria that does not have any counterpart in human cells, shikimate kinase (SK). This enzyme is essential in relevant pathogenic bacteria such as Mycobacterium tuberculosis, Helicobacter pylori and Pseudomonas aeruginosa and catalyzes the stereospecific phosphorylation of the C3 hydroxyl group of shikimic acid by transferring the γ-phosphate group of ATP to the hydroxyl group to provide shikimate 3-phosphate and ADP. Here, we report results from NMR, biochemical, structural and molecular dynamics simulation studies that help understand the catalytic mechanism of the SK enzyme. Based on these results, several competitive inhibitors of the enzyme were designed. Our recent results on this project will be presented.

Biography:

Tatsuya TAKAGI has completed his Ph.D. at the age of 32 from Osaka University.At that time, he had been an Assistant Professor of School of Pharmaceutical Sciences, Osaka University for 5 years. Then, since 1993, he had worked for the Genome Information Research Center, Osaka University as an Associate Professor until he became a professor of Graduate School of Pharmaceutical Sciences, Osaka University in 1998. He has published more than 100 papers in reputed journals and serving as Chairman of Division of Structure-Activity Relationship of the Pharmaceutical Society of Japan.

Abstract:

Since dengue virus (DENV) infection causes epidemics in tropics/subtropics, some times it causes a potentially lethal complication, dengue hemorrhagic fever. Unfortunately, there are no effective drugs or vaccines against this infection. Thus, development of drugs and vaccines against DENV is expected. Recently, we found SK-12, a novel NS2/NS3 protease inhibitor, by structure-based in Silico screening. In this study, we carried out some ligand-based in Silico screening studies forim proving the inhibitors based on the structure of SK-12. First, we defined a pharmacophore of SK-12, and then carried out a pharmacophore search using a compound database. Next, some fingerprints of SK-12 and of compounds in the same database were obtained and then a similarity search for the compounds was carried out. As the compound database, OCDD compound library provided by the University of Tokyo was used. All these calculations were operated by MOE (CCG Inc.). Finally, 80 compounds were extracted based on the docking score obtained by MOE Dock, from the compounds obtained by the abovementioned procedure. Viral replication assays and toxicity measurements of them by MTT assay showed that EC50=0.51µMfor compound 1 (SK-12,EC50=2.55µM),which indicates that compound 1 is more active than SK-12. However, in vitro protease assay of compound 1 showed no inhibitory activities against NS2B/NS3. Then we tried to search the target molecules of compound 1, which might be the novel target molecules of anti-DENV inhibitor.(This work was supported by Project MEET, Osaka University Graduate School of Medicine, and Mitsubishi Tanabe Pharma Corporation)

Biography:

Jonathan completed his PhD at the University of York in 2005 and has held postdoctoral positions at the University of Toronto (2009) and the Australian National University (2006). Jonathan is a Senior Research Scientist at Pharmaxis Ltd in Sydney Australia where he works in the drug discovery department with roles in medicinal chemistry, computer-aided drug design and project managment.

Abstract:

Human membrane primary amine oxidase (hAOC3, also known as vascular adhesion protein-1, VAP-1) is a member of the copper dependent amine oxidase family. The enzymatic function of this protein is commonly known as Semicarbazide Sensitive Amine Oxidase (SSAO), and has been shown to play a crucial role in leukocyte rolling, adhesion and migration in various disease models. The binding site of this enzyme contains a topaquinone co-factor, derived from a modified tyrosine residue, that catalyses the oxidative deamination of primary amines to aldehydes with co-committal release ammonia and hydrogen peroxide. As part of our ongoing research into inflammatory lung diseases, we decided to target this enzyme using a mechanism-based inhibitor approach. Here we present the various challenges we have had to address during development including design, selectivity over related amine oxidases, in vitro cell health considerations and most significantly, optimisation of our molecules to be true mechanism-based inhibitors with no substrate turnover. The influence of in vitro SAR profiling and computer aided drug design will be discussed.

Biography:

Ioannis Grigoriadis has completed his PharmacistD at the age of 24 years from Aristotle University of Thessaloniki and doctoral studies from University of Ioannina Medical School. He is the scientific director of Biogenea Pharmaceuticals Ltd, a premier biotechnology personalized cancer vaccination service organization. He has published more than 25 papers in reputed journals and has been serving as an editorial board member of repute.

Abstract:

Drug discovery and development is an interdisciplinary, expensive and time-consuming process. Scientific advancements during the past two decades have changed the way pharmaceutical research generate novel bioactive molecules. Advances in computational techniques and in parallel hardware support have enabled in silico methods, and in particular structure-based drug design method, to speed up new target selection through the identification of hits to the optimization of lead compounds in the drug discovery process. Glioblastoma multiforme (GBM) is the most aggressive central nervous system (CNS) tumor because of its fast development, poor prognosis, difficult control and terrible mortality. Poor penetration and retention in the glioblastoma parenchyma were crucial challenges in GBM nanomedicine therapy. The peptide, YIGSR, decreases tumor growth and experimental metastasis via a 32/67 kD receptor. The CREKA-modified PAMAM could penetrate the GBM tissue deeply and enhance the retention effect, which was a promising strategy for brain tumor therapy Researchers have also designed and synthesized novel peptides that target a deadly brain cancer, glioblastoma multiforme, by binding to the IL-13Rα2 receptor, which is highly expressed by these cancer cells. The peptides cross the blood brain barrier and strongly bind specifically to IL-13Rα2. The peptides are conjugated to one or more drugs that are toxic to cells. Upon binding specifically to brain tumor cells, the peptide-drug conjugates are internalized and then kill the tumor cells without targeting normal brain cells. Alternatively, the peptides can deliver imaging molecules that can be used to precisely diagnose brain tumors.Identification of such sites will have use in defining strategies to develop therapeutics for cancer. Protein complexes involving IDPs are short-lived and typically involve short amino acid stretches bearing few "hot spots", thus the identification of molecules able to modulate them can produce important lead compounds: in this scenario peptides and/or peptidomimetics, deriving from structure-based, combinatorial or protein dissection approaches, can play a key role as hit compounds. Multivalency is a design principle that can convert inhibitors with low affinity to ones with high avidity and/or biological "activity" gauged by some relevant parameter: (for example, values of IC50 the concentration of free ligand, often approximated as the total ligand, that reduces the experimental signal to 50% of its initial value). In addition, multivalent approaches can be effective in generating high-avidity ligands for proteins with multiple binding sites from low-affinity ligands. Multivalent ligands (primarily polyvalent ones) are especially well suited for inhibiting or augmenting interactions at biological surfaces (e. g., surfaces of bacteria, viruses, cells they can prevent adhesion of these surfaces to other surfaces by grafting polymers to the surfaces of viruses to prevent adhesion to cells). Computational docking, colchicine-tubulin competitive binding, and tubulin polymerization studies demonstrated that these compounds bind at the colchicine-binding site on tubulin and inhibit the formation of microtubules. The mode of action of the VDAC-1 peptides involves dysfunction of mitochondria energy production and apoptosis induction. In this study, we confine attention to the so called ligand-based target prediction machine learning peptide mimetic drug discovery approaches, commonly referred to as drug target fishing. Here, in Biogenea we have for the first time discovered an in silico high binding free energy affinity value predicted Novel Hyper-Multi-Targeted computer-aided Inhibitor against tumor growth and experimental metastasis related Glioblastoma conserved motif-like peptide domains.These results demonstrate that the VDAC1 treating CLL peptides may assist target-fishing approaches that are currently ubiquitous in cheminformatics and can be essentially viewed as single-label peptidomimetic drug discovery schemes. Here, we have for the first time in silico Development of a novel class of hyper-multi-targeted computer-aided CREKA/YIGSR-peptide mimotopic dual Inhibitor against tumor growth, metastasis related glioblastoma conserved motif-like peptide domains VDAC1-peptide mimetic tubulin targeted HA14-1-based multivalent chemical inhibitorory promising anticancer activities as novel in silico high binding free energy affinity value pro-apoptotic annotated agent for B-cell chronic lymphocytic leukemia.

Biography:

Paulo Paixão has a PhD in pharmacokinetics by the University of Lisbon, is an Invited Assistant Professor on Biopharmaceuticals and Pharmacokinetics at Lisbon University and a Pharmacokinetic Assessor at the Portuguese Regulatory Agency (INFARMED.PT). He focuses his research on the development and application of modelling and simulation tools for the prediction and characterization of the pharmacokinetic properties of new molecular entities and on bioequivalence issues by using QSAR and PBPK models.

Abstract:

Purpose To develop a QSAR model, based on calculated molecular descriptors and an Artificial Neural Networks Ensemble (ANNE), for the estimation of plasma protein binding (as fraction of unbound drug in plasma - fup) of drugs in human, rat, dog and monkey plasma, as well as the assessment of the applicability domain (AD) of the model. Methods A total of 680 individual fup values (75% train and 25% validation), were collected in the literature from human, rat, dog and monkey plasma concentrations. A correlation between simple molecular descriptors for lipophilicity, ionization, size and hydrogen bonding capacity and fup data was attempted by using an ANNE. Results A degradation of the correlations was observed for predicted values with high uncertainty, as judged by the standard deviations of the ANNE outputs. Based on this, a “cut-off” SD<0.0857 was establish to consider that a particular drug is inside the AD of the model. Similar statistics were observed between the train and validation group of data, when inside the AD, with correlations between the observed values and the predicted average ANNE values, of 0.951 and 0.854, respectively. 82% of the drugs were well predicted with diference of less than 0.2 in the validation group of data, again when inside the AD (93% in the train dataset). Conclusions This model may be a valuable tool for simulation and prediction in early drug development, allowing the insilico estimation of fup in different pre-clinical models and in the human, that may be used for PBPK purposes.

Biography:

Wafi Siala is a researcher in Université catholique de Louvain, Belgium

Abstract:

Objective: Staphylococcal biofilms are poorly responsive to antibiotics. In a preliminary screening of combinations of moxifloxacin (MXF) with drugs selected based on their amphiphilic character, we observed that the antifungal caspofungin (CAS)was synergistic. Our aim was now to test this combination on biofilms preformed on catheters in vitro and in vivo. Methods: Biofilms were grown inside 1cm polyurethane catheters at 37°C for 24h (initial inoculum: 5.106 cells/ml).In vitro, 7 clinical isolates and the bioluminescent Xen36 strain were used. Biofilms grown on catheters were placed in 24-well plates, incubated with MXF(10mg/L); CAS(80mg/L) or MXF/CAS for 48 h. Catheters were washed, sonicated, and CFUs/catheter were counted.Invivo,5 catheters infected with Xen36 biofilm were implanted subcutaneously in the back of mice. Animals were treated intravenously with MXF(40 mg/kg twice daily), CAS(4 mg/kg/day) or with MXF/CAS combination during 7 days. CFUs/catheter were counted.

Results: In vitro, MXF or CAS alone caused no significant decrease in CFU/catheterfor all tested strains. When combined with CAS, MXF markedly decreased CFU/catheter in all strains, but to different extents (ranging from 2 to 8.2 log CFU decrease). Invivodrugs alone were ineffective as well. The MXF/CAS combination caused a 2.1 log CFU reduction for Xen36 (vs. 3.3 log CFU reduction against the same strain in vitro). Conclusion: CombiningMXF with CASproves highly synergistic in vitro and in vivo against staphylococcal biofilms. This will open perspective to use CAS as adjuvant for the treatment of S.aureus biofilms Log CFU/catheter Strains (origin) In vitro model Untreated MXF CAS MXF-CAS 2011/S027 (cellulitis and bacteremia) 9.08±0.98 8.82±0.24 9.14±0.17 1.43±0.36a 2003/1083 (chirurgical wound) 11.7±0.32 11.5±0.14 12.3±0.21 3.41±0.09a 2005/104 (skin) 6.87±0.32 6.51±0.44 6.99±0.22 3.01±0.32a 2009/S028 (nasal carriage) 6.88±0.22 6.45±0.12 6.78±0.09 2.70±0.15a 2009/S025 (ear) 8.12±0.44 8.16±0.99 8.47±0.45 3.55±0.14a 2005/179 (skin) 6.73±0.65 6.55±0.11 6.77±0.12 2.69±0.06a 2003/651 (respiratory infection) 5.44±0.82 4.19±0.15 5.47±0.08 3.57±0.07 a XEN36 (bioluminescent derived from S.aureus ATCC 49525) 6.26±0.22 6.23±0.32 6.35±0.14 2.91±0.65a In vivo model XEN36 7.31±0.45 6.17±0.13 7.35±0.42 5.15±0.15 b statistical analysis :comparison between MXF treated group and MXF-CAS treated group for each strain ain vitro data; P value ≤0.01 for all strains bin vivo data; P value =0.028

Biography:

Ioannis Grigoriadis has completed his PharmacistD at the age of 24 years from Aristotle University of Thessaloniki and doctoral studies from University of Ioannina Medical School. He is the scientific director of Biogenea Pharmaceuticals Ltd, a premier biotechnology personalized cancer vaccination service organization. He has published more than 25 papers in reputed journals and has been serving as an editorial board member of repute.

Abstract:

Drug discovery and development is an interdisciplinary, expensive and time-consuming process. Scientific advancements during the past two decades have changed the way pharmaceutical research generate novel bioactive molecules. Advances in computational techniques and in parallel hardware support have enabled in silico methods, and in particular structure-based drug design method, to speed up new target selection through the identification of hits to the optimization of lead compounds in the drug discovery process. Glioblastoma multiforme (GBM) is the most aggressive central nervous system (CNS) tumor because of its fast development, poor prognosis, difficult control and terrible mortality. Poor penetration and retention in the glioblastoma parenchyma were crucial challenges in GBM nanomedicine therapy. The peptide, YIGSR, decreases tumor growth and experimental metastasis via a 32/67 kD receptor. The CREKA-modified PAMAM could penetrate the GBM tissue deeply and enhance the retention effect, which was a promising strategy for brain tumor therapy Researchers have also designed and synthesized novel peptides that target a deadly brain cancer, glioblastoma multiforme, by binding to the IL-13Rα2 receptor, which is highly expressed by these cancer cells. The peptides cross the blood brain barrier and strongly bind specifically to IL-13Rα2. The peptides are conjugated to one or more drugs that are toxic to cells. Upon binding specifically to brain tumor cells, the peptide-drug conjugates are internalized and then kill the tumor cells without targeting normal brain cells. Alternatively, the peptides can deliver imaging molecules that can be used to precisely diagnose brain tumors. Identification of such sites will have use in defining strategies to develop therapeutics for cancer. Protein complexes involving IDPs are short-lived and typically involve short amino acid stretches bearing few "hot spots", thus the identification of molecules able to modulate them can produce important lead compounds: in this scenario peptides and/or peptidomimetics, deriving from structure-based, combinatorial or protein dissection approaches, can play a key role as hit compounds. Multivalency is a design principle that can convert inhibitors with low affinity to ones with high avidity and/or biological "activity" gauged by some relevant parameter: (for example, values of IC50 the concentration of free ligand, often approximated as the total ligand, that reduces the experimental signal to 50% of its initial value). In addition, multivalent approaches can be effective in generating high-avidity ligands for proteins with multiple binding sites from low-affinity ligands. Multivalent ligands (primarily polyvalent ones) are especially well suited for inhibiting or augmenting interactions at biological surfaces (e. g., surfaces of bacteria, viruses, cells they can prevent adhesion of these surfaces to other surfaces by grafting polymers to the surfaces of viruses to prevent adhesion to cells). Computational docking, colchicine-tubulin competitive binding, and tubulin polymerization studies demonstrated that these compounds bind at the colchicine-binding site on tubulin and inhibit the formation of microtubules. The mode of action of the VDAC-1 peptides involves dysfunction of mitochondria energy production and apoptosis induction. In this study, we confine attention to the so called ligand-based target prediction machine learning peptide mimetic drug discovery approaches, commonly referred to as drug target fishing. Here, in Biogenea we have for the first time discovered an in silico high binding free energy affinity value predicted Novel Hyper-Multi-Targeted computer-aided Inhibitor against tumor growth and experimental metastasis related Glioblastoma conserved motif-like peptide domains. These results demonstrate that the VDAC1 treating CLL peptides may assist target-fishing approaches that are currently ubiquitous in cheminformatics and can be essentially viewed as single-label peptidomimetic drug discovery schemes. Here, we have for the first time in silico Development of a novel class of hyper-multi-targeted computer-aided CREKA/YIGSR-peptide mimotopic dual Inhibitor against tumor growth, metastasis related glioblastoma conserved motif-like peptide domains VDAC1-peptide mimetic tubulin targeted HA14-1-based multivalent chemical inhibitorory promising anticancer activities as novel in silico high binding free energy affinity value pro-apoptotic annotated agent for B-cell chronic lymphocytic leukemia.

Biography:

Luis Manzano is a chemist laboratory technician. His work in the biochemistry laboratory at Escuela Superior de Medicina is to synthesize several compounds derivatives of phenylethylamine and perform the characterization of these molecules. Currently, he is at the first semester in biochemical engineering atEscuela Nacional de CienciasBiologicas ofInstitutoPolitecnico Nacional.

Abstract:

The Cyclooxygenase-II (COX-II) is a protein encoded by the human gene PTGS2 present in inflammatory processes. The role of COX-II is to mediate inflammation processes and prostaglandin biosynthesis from arachidonic acid. No steroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed for the treatment of acute or chronic inflammation and offer symptomatic pain relief by inhibiting the COX-II. Most NSAIDs currently used in clinic are known to inhibit both isoforms of Prostaglandins H synthase (PGHS) with little selectivity, and during extended therapy many NSAIDs cause ulcerogenic side effects most likely due to PGHS-1 inhibition in the stomach. The structural observations in regard to the pharmacological effect of phthalimides promoted our interest to synthesize a novel series of dioxoisoindoline and investigating the anti-inflammatory activity of these compounds to COX-2 enzymes through in silico studies. We performed the molecular approach (docking) of 29 dioxoisoindolines derived of primary amines. The results showed that the best ligands were the molecules Do15-1, Do15-16 and Do15-17S with a ΔG of -8.24, -9.46 and -8.17 Kcal/mol respectively, showing a high affinity to interact with Cyclooxygenase-II. Therefore, those 3 ligands were synthesized with a green synthesis technique and their structures were confirmed by infrared spectroscopy, nuclear magnetic resonance and mass spectroscopy. In addition to the insilico results we plan to perform in vivo experiments with Sprague Dawley rats and BALB/c mice with our synthesized compounds, in order to test their possible inhibitory activity toward COX-II and their possible effects on the gastric mucosa.

Biography:

Barbara Susana Gregori Vlades is student of PhD in University o Lisbon , Pharmacy Faculty. She integrates the Nanomedicine and Drug Delivery Systems (nanoDDS) group of the Research Institute for Medicines and Pharmaceutical Sciences (iMed. FFUL), and collaborates with other research teams from Instituto Superior Tecnico and IFAL, University of Havana. She has published several papers in journals and has been serving as an editorial board member of repute

Abstract:

This study focused on the synthesis and characterization of a polyurethanes to prepare a nail lacquer formulation with terbinafine hydrochloride in order to obtain a topical nail release system The synthesis of polymer was carried out by the reaction of of IPDI, PPG and isosorbide with 6:1:5 ratio, under a nitrogen atmosphere using 0.5 mL of DABCO as catalyst. The polymer was characterized by FTIR, NMR, DSC PALS and the biocompatibility with keratinocytes cell was study.The in vitro release profile of terbinafine from diferent nail lacquer formulatios was investigated using Franz Cells. The FTIR spectrum showed a band at 1695 cm-1 attributed to the stretching vibration of the C=O carbonyl of urethane. The PU melting temperature was around 60 oC. The presence of -NH protons at 5.2 and 7.5 ppm in the 1H NMR spectrum in dmso confirm the reaction between the isosorbide hydroxyl groups and the pre-polymer isocyanate groups. The PU presents cell viability measured by the MTT reduction. The release profile, demonstrated that the formulation had the ability to release the drug. In this research new polyurethane was synthesized and characterized. The polyurethane synthesized presented biocompatibility. The results so far obtained are promising for a novel terbinafine based nail lacquer for the treatment of fungal infections

Biography:

Hafiz Ansar Rasul Suleria is a researcher in The University of Queensland, Australia

Abstract:

Marine organisms are increasingly being investigated as sources of bioactive molecules with therapeutic applications as nutraceuticals and pharmaceuticals. Recent trends in functional foods have demonstrated that bioactive molecules play a major therapeutic role in human disease, therefore nutritionists, biomedical scientists and food scientists are working together to discover new bioactive molecules that have increased potency and therapeutic benefits. Marine life constitutes almost 80% of the world biota with thousands of bioactive compounds and secondary metabolites derived from marine invertebrates such as tunicates, sponges, mollusks, sea hares, bryozoans, sea slugs and other marine organisms. These bioactives and secondary metabolites possess antibiotic, anti-parasitic, anti-viral, anti-inflammatory, anti-fibrotic and anti-cancer activities. They are inhibitors or activators of critical enzymes, agonists or inhibitors of transcription factors, competitors of transporters and sequestrants to modulate various physiological pathways. The current review summarises the widely available marine-based nutraceuticals and recent findings, mainly focusing on mode of action, efficacy and underlying mechanisms. It also presents recent research involving the isolation, identification and characterization of marine-derived bioactives with various therapeutic potentials.

Biography:

Yue-Wei Guo is a is a researcher in Chinese Academy of Sciences, China

Abstract:

Mangroves comprise a large number of various salt-tolerant plants growing in tropical and subtropical intertidal estuarine zones. Historically, many mangrove plants were used to treat various diseases in traditional Chinese medicine. Currently, the secondary metabolites found in Mangroves represent an extremely rich source of novel chemical diversity for academic drug discovery and chemical biology programs. It is particularly true that the mangroves from Southern Coast of China are very prolific producers of bioactive natural products.1 Our group at SIMM has long been engaged in the searching for novel secondary metabolites with pharmacological potential from Chinese mangrove medicinal plants.2 In collaboration with biologists and pharmacologists at SIMM, many mangroves used as fork medicine were chemically investigated and numerous novel isolates obtained were pharmacologically screened for activity in a variety of cell-based and pure enzyme assays designed to identify promising lead compounds for the development of drugs in the therapy of human diseases.3 This presentation will discuss examples of bioactive metabolites (structures and activities) from our recent discovery efforts.

Biography:

Yue-Wei Guo has completed his PhD at the age of 39 years from Naples University, Italy and postdoctoral studies from Istituto di Chimica Biomoleculare-CNR, Italy and Hokkaido University School of Pharmacy, Japan. He is the principal investigator of marine natural products Lab in SIMM, a premier drug R & D organization in China. He has published more than 320 papers in reputed journals and serving as an editorial board member of repute.

Abstract:

The steroids found in Hainan benthic marine invertebrates represent an extremely rich source of novel chemical diversity for academic drug discovery and chemical biology programs. It is particularly true that the benthic invertebrates, such as sponges, soft corals, from southern coast of China are very prolific producers of bioactive steroid natural products. Our group at SIMM-CAS has long been engaged in the searching for novel secondary metabolites, including steroids, with pharmacological potential from Chinese marine animals. In collaboration with biologists and pharmacologists at SIMM, many marine invertebrates were chemically investigated and numerous novel isolates obtained were pharmacologically screened for activity in a variety of cell-based and pure enzyme assays designed to identify promising lead compounds for the development of drugs in the therapy of human diseases. This presentation will discuss examples of biologically active and structurally interesting steroids from our recent discovery efforts

Biography:

Akbar Hedayatizadeh-Omran is a researcher in University of Medical Sciences, Iran

Abstract:

Several diseases are associated with oxidative stress caused by free radicals and reactive oxygen species. In this study, antioxidant activity of captopril was studied using in vitro assays systems. Free radical scavenging and reducing power were determined with diphenyl picryl hydrazyl free radical (DPPH method) and potassium ferricyanide method, respectively. The results of this study showed that captopril possessed a significant free radical scavenging and reducing power properties and there were a clear correlation exists between antioxidant activity and concentration of captopril. Percentage of free radical scavenging of captopril was more than 92 % at concentration 0.08 mM

Biography:

I am Sara Nasrollahi, I am graduated from master of science in applied chemistry at age of 25 from Islamic Azad University Central Tehran Branch, Tehran, Iran. I have published two papers in well-known journals about drug delivery and one paper about environmental chemistry. I also have studied on adsorbing heavy metals from environmental water samples and biological solution, and written some papers which are under revision.

Abstract:

A novel method is reported for grafting of poly [N-isopropylacrylamide-co-allylglycidyl/iminodiacetic] based on iron oxide nano-particles modified by 3-mercaptopropyltrimethoxysilane. The grafted nano-polymer was characterized by elemental analysis, Fourier transform infrared spectroscopy, thermogravimetric analysis, transmission electron microscopy and scanning electron microscopy. The analytical parameters such as pH, temperature and contact time of the grafted nano-polymer were studied. Determination and extraction of famotidine in human biological fluids were evaluated with high great accessibility to the active sites in the grafted sorbent. The equilibrium adsorption data of famotidine by grafted nano-sorbent were analyzed by Langmuir and Freundlich models. The sorption capacity of the nano-sorbent was 116 mg g-1 at an optimum pH of 7. Almost 73% of famotidine was released in simulated gastric fluid in 1 h and 70% was released in simulated intestinal fluids in 30 h at 37ËšC. These results show that this new magnetic grafted nano-polymer is adequate for enteric drug delivery. The suitable cause for choosing this particular polymer was its strong retention and subsequently longer controlled release for drug delivery. In other investigation, the effect of temperature on famotidine release was evaluated. The sorption and desorption studies were carried out at five temperatures (25-45°C). The results showed that the maximum adsorption of famotidine occurred at 30°C. Because, at low temperatures, the repeating chains of N-isopropylacrylamide on the nano-sorbent were in expanded form and famotidine better loaded onto the sorbent. At high temperature the grafted polymer containing the thermo-sensitive monomer shrank, so the release of famotidine increased.

Biography:

Kian Navaee has completed his M.Sc in organic chemistry at the age of 28 years from Institute for Advanced Studies in Basic Sciences (IASBS) in Iran. He is supervisor in research and development Department of Shahre Daru Pharmaceutical Co. in Iran. His scientific research articles cited more than 225 papers in ISI journals to present. He is full member of the American Chemical Society (ACS).

Abstract:

Artificial neural networks (ANNs) technology models the pattern recognition capabilities of the neural networks of the brain. Similarly to a single neuron in the brain, artificial neuron unit receives inputs from many external sources, processes them, and makes decisions. Interestingly, ANN simulates the biological nervous system and draws on analogues of adaptive biological neurons. ANNs do not require rigidly structured experimental designs and can map functions using historical or incomplete data, which makes them a powerful tool for simulation of various non-linear systems. ANNs have many applications in various fields, including engineering, psychology, medicinal chemistry and pharmaceutical research. Because of their capacity for making predictions, pattern recognition, and modeling, ANNs have been very useful in many aspects of pharmaceutical research including modeling of the brain neural network, analytical data analysis, drug modeling, protein structure and function, dosage optimization and manufacturing, pharmacokinetics and pharmacodynamics modeling, and in vitro in vivo correlations. These presentations will discuss the applications of ANNs in drug delivery and pharmacological research.

Biography:

Bin Xu received his Ph.D. from Case Western Reserve University in 2004; and followed by postdoctoralstudies at Fred Hutchinson Cancer Research Center. Since 2011, he has beena tenure-track Assistant Professor in the Department of Biochemistry and Center for Drug Discovery at Virginia Tech. His research interests concern cell surface receptor-ligand binding, receptor signaling, novel ligand and receptor discovery, and translational structure-based and computer-aided ligand design with applications to novel peptide hormones and natural products relevant to diabetes, obesity,neurodegenerative diseases, and nanomedicine. He has published more than two dozens publications in premier international peer-reviewed journals.

Abstract:

The incidence of type 1 diabetes (T1D) is increasing fast worldwide and currently there is no known cure for this disease. Past studies provided encouraging evidence that b-cells have the potential to regenerate primarily by proliferation of existing b-cells. Through performing a systematic screen of a natural products collection, we discovered that oleuropein, a natural compound typically found in olive leaf and fruit and olive oil, induces b-cell growth and potentiates glucose stimulated insulin secretion. Oleuropein is shown to stimulate INS1 b-cell proliferation following a 24 hour incubation period as determined by bromo-deoxyuridine (BrdU) DNA incorporation-based cell replication assay and tetrazolium MTT-based cell proliferation assay. The effect of oleuropein on β-cell growth is as potent as that of glucagon-like peptide, a known FDA-approved type 2diabetes drug. To determine the molecular mechanisms by which oleuropein induces b-cell growth and exerts its potential anti-diabetes effects, we have performed detailed signaling analyses. Our results show that oleuropein acutely (within the time-frame of 20 minutes of treatment) activated ERK1/2 in INS1 cells. Using pharmacological inhibitors, we found PD98059, a known MEK1/2 inhibitor, strongly diminished ERK phosphorylation induced by oleuropein. To further map pathways upstream of ERK-MEK, we applied a panel of inhibitors. We found small compound Sorafenib (BAY 43-9006), a kinase Raf inhibitor, significantly inhibits oleuropein-induced ERK phosphorylation. Treatments of PKA inhibitors KT5720 or H89, PI3K inhibitor LY294002, AMPK inhibitor compound C each had no significant effects. We conclude oleuropein promotes b-cell proliferation through ERK-MEK-Raf pathway.

Biography:

Olalude C.B is a researcher in The polytechnic Ibadan, Nigeria

Abstract:

Daucus Carota popularly known as Carrot is one of the most popular Root Vegetables grown throughout the World and it is one of the most important Carotenoids. Carrots are credited with many medicinal properties, they are said to cleanse the intestines and to be Diuretic, Revitalizing, Antidiarrheal, Antianemic and rich in alkaline Elements which purify and Revitalize the Blood. It also has a Repution as a Vegetable that helps to maintain good eyesight. The results of the Physicochemical Analysis of Carrot Juice was analyzed and this result showed that the moisture content is 91.000 ± 0.265 which indicates that carrot contained much water which will help in healthy hydration of the body system, in transport of nutrient, elimination of waste and body temperature regulation .protein % 1.067 ± 0.058, which indicates that carrot will serve as a collagen for supportive tissue, Heamoglobin for transport, antibodies for immune defense and enzymes for metabolism in the body and can serve as balanced diet in humans. ether extract ( crude fat) % 0.367 ± 0.089 this shows that carrot is not rich in oil i.e. does not contain much oil, ash % 1.333 ± 0.153 this means that carrot contains essential nutrient elements, as this will normally show up in the ash content of a vegetable matter and can be used to argument minerals in food formulation. crude fibre % 1.167 ± 0.153 crude fibre is desirable in meals, as they serve as digestion aids, carbohydrate % 6.100 ± 0.346 this indicate that carrot can be used as food supplement sources of carbohydrate or energy, specific gravity 1.069 ± 0.003,pH 6.333 ± 0.058,ascorbic acid 16.667 ± 1.332, Ca++ (mg/100g) 55.000 ± 0.000, Fe++( mg/100g)1.667 ± 0.153, PO4—( mg/100g)44.333 ± 1.155, thiamine (mg/100g) 0.057 ± 0.006, niacin(mg/100g) 0.300 ± 0.000, riboflavin 0.100 ± 0.000,β-carotene 2730 ± 43.589,colour (out of 10) 2.000 ± 0.000 and vitamin A 2805 ± 6.532. The results shown that vitamin A and β carotene has high content in carrot juice. As a result of these findings, carrot is save for consumption without passing any negative or deleting effect to its consumer, consumption of it should be encourage because of its health benefits.

Biography:

Currently, I am working as Assistant Professor at the Department of Biochemistry, University of Karachi, earlier completed by PhD from King’s College London, UK in 2011 in the field of Computational Biophysics. My field of specialization is “Computer Aided Drug Design”, which I teach at graduate and postgraduate level. I have supervised more than 10 Master’s thesis and also published more than 12 research articles in various scientific journals.

Abstract:

Data on phytochemical constituents of herbs commonly used in traditional Indonesian medicine have been compiled as a database using ChemDBSoft software. This database (the Indonesian Herbal constituents database, IHD) contains details on 1,242 compounds found in 33 different plants. For each entry, the IHD gives details of chemical structure, trivial and systematic name, CAS registry number, pharmacology (where known), toxicology (LD50), botanical species, the part(s) of the plant(s) where the compounds are found, typical dosage(s) and reference(s). A second database has been also been compiled for plant-derived compounds with known activity against the enzyme, aldose reductase (AR). This database (the aldose reductase inhibitors database, ARID) contains the same details as the IHD, and currently comprises information on 112 different AR inhibitors. In the search for novel leads active against AR to provide for new forms of symptomatic relief in diabetic patients – virtual screening of all compounds in the IHD has been performed using (a) random forest (RF) modelling, and (b) molecular docking. For the RF modelling, 3 sets of chemical descriptors – Constitutional, RDF and 3DMoRSE (computed using the DRAGON software) were employed to classify all compounds in the combined ARID and IHD databases as either active or inactive as AR inhibitors. The resulting RF models (which give misclassification rates of ~10%) were used to identify putative new AR inhibitors in the IHD, with such compounds being identified as those giving a mean RF score > 0.5. Virtual screening of the IHD was also performed using the docking software, Molegro Virtual Dokcer (MVD), In the docking studies reported here, carboxyl-containing IHD compounds were docked in to the active site of the 11 crystal structures of AR bound to different carboxyl containing ligands. Calculation of the averages of these 11 MVD re-rank scores was carried out as a means to identify anomalous docking results. In-vitro assays were subsequently performed to determine the inhibitory activity against human recombinant AR for four of the compounds obtained as hits in RF in-silico screenings and for a further four compounds obtained as hits in the docking studies. All four of the RF and docking hits were (as predicted) active as AR inhibitors with IC50s in the micromolar range.

Biography:

Dr. Sumeet Dwivedi has obtained his B.Pharm from Smriti College of Pharmaceutical Sciences, Indore, M.P., M.Pharm (Pharmacognosy), with Hons./Gold Medal from Vinayaka Missions University, Salem, T.N., Pursuing Ph.D. from Suresh Gyan Vihar University, Jaipur, R.J., presently working as Associate Professor and Head of the Department, Chordia Institute of Pharmacy, Indore, M.P. He is involved in research on screening, formulation, standardization of herbals, cultivation practices of medicinal plants, biotechnological approaches of herbs. He has his credit of more than 150 research/review papers in various national and international Journal of repute, has more than 50 Abstract in various Conferences, published 6 books and serving as Executive Editor, International Journal of Pharmacy and Life Sciences and Managing Editor, International Journal of Drug Discovery and Herbal Research, Reviewer of many Journals and Editorial Board Member of various Journal.

Abstract:

India is one of the richest reservoirs of biological diversity in the world. It is home to a great variety of ethno-medicinally important plant species, and is ranked 6th (sixth) among 12 mega diversity countries of the world. However, several factors are putting India’s medicinal plants at risk of extinction: the increasing demand for herbal raw-material & products, the reliance of pharmaceutical companies on plants for drugs, the encroachment of civilization into plant habitat (including timber and mining operations, shopping malls and housing developments), and the innate sensitivity or rareness of certain species. The problems are compounded by market-demand driven harvesting without any concern for representation and conservation. In the process essential regenerative components of a plant like roots, tubers, fruits, seeds, flowers and bark are indiscriminately collected, leading to degradation and depletion and even extinction of particular species. Due to this ruthless exploitation, many important medicinal plants species are becoming rare and some of them are critically endangered. The present paper deals with the need of several standardization parameters of some endangered medicinal plants of Central India. Several validation parameters such as LOD, FOM, TA, SI, HPTLC fingerprint etc were highlighted in the present communications.