Scientific Program

Conference Series Ltd invites all the participants across the globe to attend 4th International Conference on Medicinal Chemistry & Computer Aided Drug Designing Atlanta, USA.

Day 1 :

Keynote Forum

Concepción González-Bello

Universidad de Santiago de Compostela
Spain

Keynote: Covalent inhibition of bacterial type I dehydroquinase – Opportunities for anti-virulence therapies

Time : 10:00-10:00

Conference Series MedChem & CADD-2015 International Conference Keynote Speaker Concepción González-Bello photo
Biography:

Concepción González-Bello has obtained her PhD at the University of Santiago de Compostela (USC, Spain) in 1994. She did two predoctoral stays in thernUniversity of Gent (Belgium) with Prof. Vandewalle and in the Scripps Research Institute (USA) with Prof. Nicolaou. After a postdoctoral stay in the University ofrnCambridge (UK) with Prof. Abell, she joined USC as an Assistant Professor, and was promoted to Associate Professor in 2003 and obtained the Spanish habilitationrnto full Professor in 2011. In 2011, she joined the CIQUS, a new USC research center, as a group leader. She is author of about 70 papers and several patents andrnbook chapters.

Abstract:

The loss of effectiveness of current antibiotics caused by the development of drug resistance, along with the evident decline in antibiotic research by the major pharmaceutical companies during the last 50 years, has triggered the search for novel antibiotics and alternative therapies. Targeting bacterial virulence is an attractive choice that is increasingly being explored. The inhibition of virulence factors will lead to a loss of the ability of bacteria to cause infection in the host and, as a consequence they could be more easily eliminated by the immune system. A promising target for the development of new anti-virulence agents is the type I dehydroquinase enzyme (EC 4.2.1.10, aroD gene, DHQ1). This enzyme does not have any counterpart in human cells and seems to act as a virulence factor in vivo as the deletion of the aroD gene has been proven to afford satisfactory live oral vaccines. In this talk, several irreversible inhibitors of this enzyme that cause the covalent modification of the DHQ1rnfrom Salmonella typhi and Staphylococcus aureus and that are able to reduce the ability of Salmonella enteritidis to kill A459rnrespiratory cells will be presented. The resolution of diverse crystal structures of DHQ1 from Salmonella Typhi chemically modified by those compounds, the detection by mass spectroscopy of the reaction intermediates, in conjunction with the results of molecular dynamics simulations, allowed us to explain the inhibition mechanism of those compounds. Our recent results on this project will be presented

Conference Series MedChem & CADD-2015 International Conference Keynote Speaker Carsten Detering photo
Biography:

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 Washingtonrnin 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 herncame 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,rnbefore moving back to Seattle as CEO of BioSolveIT Inc, the North American subsidiary of BioSolveIT.

Abstract:

The borders between traditional medicinal chemists and computational chemists have been blurred in the past 10 years. Medicinal chemists today are much more likely to assume more and more computational tasks. This entails crafting more intuitive software from the software industry, and also the seamless integration of 2D SAR data with 3D structural information to combine the medicinal chemist’s view of things with that of the computational chemist. This talk will highlight how we can utilize information from 2D ADME/T property models and 3D views of protein-ligand complexes. A glimpse into the near future will show how the influence of each atom or functional group on these properties can be highlighted and combined with visualization of the atomistic contributions to binding affinity. This enables development of optimization strategies that balance potency with the ADMET properties required in a safe and efficacious drug, thus giving this phase of the pipeline more efficiency by means of a truly multi-parameter optimization environment.

  • Novel Drug Design
Speaker
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.

Speaker
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.

Speaker
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.

Speaker
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.

Yen-Fang Wen

Industrial Technology Research Institute
Taiwan

Title: Prodrug Design and Synthesis of Oxyresveratrol to Improve Bioavailability
Speaker
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.

Speaker
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.

Speaker
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.

Speaker
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.

Speaker
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.

Yaser Rihan

Atomic Energy Authority
Hot Lab Centre
Egypt

Title: Computer Simulation of Electrostatic Micropump
Speaker
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.

Speaker
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.

Speaker
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.

  • Computer Aided Drug Design-CADD

Session Introduction

Thorsten Nowak

C4X Discovery
Manchester
United Kingdom

Title: Discovery of Novel Orexin-1 Selective Antagonists using NMR Guided Conformational Design
Speaker
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.

Speaker
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.

Speaker
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.

Speaker
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

Speaker
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.

Speaker
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).

Speaker
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.

Prasad V. Bharatam

National Institute of Pharmaceutical Education and Research
India

Title: Design of Anti-Malarial Agents Using Quantum Medicinal Chemistry Methods
Speaker
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.