Day 2 :
Keynote Forum
Thorsten Nowak
C4X Discovery
United Kingdom
Keynote: Conformational Design and its importance in drug discovery
Time : 10:00-10:30
Biography:
Thorsten Nowak completed his PhD from the University of Cambridge (UK) in the areas of aldol methodology and natural product synthesis. In 1996, he joinedrnAstraZeneca where he worked on all stages of drug discovery in medicinal chemistry as Team Leader and Project Manager. His keen interest in new technologiesrnmotivated a career move in 2012, when he joined C4X Discovery. Since he joined C4X, he has been instrumental in expanding the capabilities of C4X into appliedrndrug discovery. In his current role as Head of Medicinal Chemistry, he is leading the chemistry group and is responsible for all internal drug discovery effortsrnconducted at C4X as well as program work with our pharmaceutical partners.
Abstract:
One of the key drivers in applied medicinal chemistry which is often referred to is property based multifactorial design, at the core of which is the endeavour to harmonize a number of workflows into one. Optimization of potency, selectivity as well as ADMET properties is complex as a result of its high degree of multi-dimensionality and interdependences. Throw into the mix the question how conformations of molecules impact on properties of molecules and it becomes an almost intractable problem to solve rationally it seems. However, it is argued that detailed understanding of molecular shapes as well as the impact factors which lead to diverse conformational behaviours and the targeted manipulation of shape preferences, conformational design, are potentially an important opportunity to harness efficiencies and could make designs more effective. The talk will aim to make a case why conformational design is important, assesses some of the principals, which rationalize targeted manipulation of conformational preferences and the impact of them on biological properties of molecules.
Keynote Forum
Tatsuya Takagi
Osaka University
Japan
Keynote: Screening novel HIV-1 inhibitors targeting cyclophilin A by structure-based and ligand-based in silico study
Time : 10:30-11:00
Biography:
Tatsuya Takagi has completed his PhD from Osaka University. At that time, he had been an Assistant Professor of School of Pharmaceutical Sciences, OsakarnUniversity for 5 years. Then, since 1993, he had worked for the Genome Information Research Center, Osaka University as an Associate Professor until he becamerna Professor of Graduate School of Pharmaceutical Sciences, Osaka University in 1998. He has published more than 100 papers in reputed journals and serving asrnChairman of Division of Structure-Activity Relationship of the Pharmaceutical Society of Japan.
Abstract:
Since cyclophilin A has peptidyl-prolyl isomerase activity and binds to the capsid protein of Human Immunodeficiency Virus (HIV), it is an attractive target as an anti-HIV drug. However, just a few drugs against HIV-1 infection targeting cyclophilin A have been developed and none of them has been approved. We found a number of active compounds by in silicon structure-based screenings applying to the database with 1, 300 compounds recently. Although we found three docking sites A, B, and C, using MOE alpha site finder module, we used all of them as the docking sites because the three pockets were small. Two compounds, 12 and 23, were obtained as the most active ones. 12 covered the two docking sites, B and C, by cation-π interactions while the other covered B and C by CH-π and hydrogen bond. Especially, both of them exhibited anti-HIV activity against viral replication at low concentrations and relatively low cytotoxicity at the effective concentrations inhibiting viral growth by 50 %. As the results of comparisons between the obtained two compounds and the two controls which were called D4 and FD8, our compounds showed better results.
- Advanced Medicinal Chemistry
Session Introduction
Victor J. Hruby
University of Arizona USA
Title: Design of Novel, Selective and Bioavailable Ligands for Closely Related Receptors and Pharmacophores: Conformational and Topographical Considerations
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.
Yanli Wang
National Institutes of Health
USA
Title: PubChem BioAssay: a public information resource supporting medicinal chemistry and drug discovery research
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
Maia Merlani
Tbilisi State Medical University
Georgia
Title: Natural biopolymer-Poly[3-(3,4-dihydroxyphenyl)glyceric acid] from comfrey and its synthetic analogues
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.
Anna Hirsch
Stratingh Institute for Chemistry University of Groningen The Netherlands
Title: Small-molecule modulators of thiamine transport in pathogenic bacteria
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.
Ling Qiu
Jiangsu Institute of Nuclear Medicine
China
Title: General Anesthetics Interaction with Pentameric Ligand-Gated Ion Channel GLIC: Insights from ONIOM Calculations
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.
Seema Dhail
Bar-Ilan University
Israel
Title: QSAR Models for Cdk/Cyclin Inhibitors: A Comparison Between QM And Classical Descriptors
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
Keiko Ikemoto
Iwaki Kyoritsu General Hospital Japan
Title: TAAR1 ligands as prospective neuroleptics: From D-neuron study
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.
Byran Gowramma
JSS College of Pharmacy India
Title: SYNTHESIS & ANTI-IMFLAMMATORY SCREENING OF SOME NOVEL 2-AZETIDINONES/4-THIAZOLIDINONES BEARING 1, 3, 4-THIADIAZOLE NUCLEUS
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.
Bharathkumar Inturi
JSS College of Pharamcy India
Title: PROTEIN LIGAND BASED PHARMACOPHORE MODELING: A SEARCH FOR NOVEL MYCOBACTERIUM TUBERCULOSIS InhA INHIBITORS
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.
Divyanshu Sharma
Rajiv Academy For Pharmacy India
Title: SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME NEWER CARBAZOLE DERIVATIVES
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.
- Materialistic Chemistry & Synthetic Chemistry
Session Introduction
Carsten Detering
BioSolveIT Inc., USA
Title: How close are we to predicting binding affinity?
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).
- Drug Design and Chemistry: Cancer Studies
Session Introduction
Yong-Hwan Lee
Louisiana State University
USA
Title: Epi-drug development targeting human G9a H3K9 methyltransferase
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.
Andreia Valente
Faculdade de Ciências da Universidade de Lisboa Lisboa Portugal
Title: On the mode of action of new promising anticancer agents: multifunctional polymer-ruthenium conjugates
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.
Alessandra Nurisso
University of Geneva
Switzerland
Title: Identification of sirtuin inhibitorsas promising anticancer agents: from screening to activity assays
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.
Hamed I. Ali
Irma Lerma Rangel College of Pharmacy
USA
Title: Synthesis, Structural Anticancer Activity Relationship, and Docking Study of Novel 5-Deazaflavin Analogs
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.
Maria Helena Garcia
Faculdade de Ciências da Universidade de Lisboa Universidade de Lisboa Portugal
Title: Ruthenium drugs for cancer therapy: small structural changes, different in vivo performances
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.
Zechariah G Marting
The University of
Sydney
Australia
Title: Targeting the ‘Oligomerization Region’ of the Epidermal Growth Factor Receptor (EGFR) Using Small Molecules as Novel Anticancer Agents
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.
Anjala. W. Bulathge
University of Peradeniya
Sri Lanka
Title: Hollow calcium carbonate nanoparticles as pH-sensitive targeted delivery carriers in cancer therapy
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.
M. Thirumala Chary
JNTUH College of Engineering, Nachupally
India
Title: Synthesis and Antibacterial Activity of Some New Quinaxaline-Benzohydrazides
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.
Garcia Gamez Jesus
Escuela Superior de Medicina del Instituto Politécnico Nacional
Mexico
Title: Molecular docking and in vitro assay of isoindolina-1,3-dione amine derivative as novel HDAC8 inhibitor for cancer treatment
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.
- Neurodegenerative Diseases
Session Introduction
Alicia Merlino
Theoretical and Computational Chemistry Group
Uruguay
Title: Nitrones as potential therapeutic agents against Alzheimer’s Disease
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.
Erik Andrade Jorge
Instituto Politecnico Nacional
Mexico
Title: 2,3-dihydro-1H-isoindoline derivatives as novel drugs for Parkinson’s disease: in silico and an in vivo evaluation
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.