MedChem & CADD-2013 · 2014. 5. 24. · Page 29 2nd nternationa onference on Medicinal Chemistry Computer Aided Drug Designing October 15-1, 2013 Hampton Inn Tropicana, Las Vegas,

Page 27

2nd International Conference on

October 15-17, 2013 Hampton Inn Tropicana, Las Vegas, NV, USA

Medicinal Chemistry &Computer Aided Drug Designing

144th OMICS Group Conference

MedChem & CADD-2013

Scientific Tracks & Abstracts

1: Rational Drug Designing

Track 1Day 1 October 15, 2013

Session ChairVictor J. HrubyUniversity of Arizona, USA

Session Co-ChairAlexander HeifetzEvotec (UK) Ltd., UK

Title: Design and investigation of multivalent ligands for the detection and treatment of diseasesVictor J Hruby, University of Arizona, USA

Title: Structure based drug discovery for GPCRs: From receptors to ligandsAlexander Heifetz, Evotec (UK) Ltd., UK

Title: DNA binding polyamides designed against E1, E2 binding sites of HPV DNA show dramatic anti-HPV activity in cell and tissue cultureJames K Bashkin, University of Missouri-St. Louis, USA

Title: Structure-guided design, synthesis, and evaluation of guanine-derived inhibitors of the eIF4E mRNA-cap interactionXiaoqi Chen, Amgen, USA

Title: The design and discovery of CXCR4 chemokine receptor antagonists through incorporation of GPCR-MedChem based fragmentsLarry Wilson, Emory University and Emory Institute for Drug Development, USA

Title: Understanding the essential requirements for success in structure-based designGregory L Warren, OpenEye Scientific Software, USA

Title: Site Identification by Ligand Competitive Saturation (SILCS): Computational approach for the identification and optimization of ligands targeting proteins, RNA and other macromoleculesAlexander D MacKerell, University of Maryland, USA

Title: Computer-aided design of glucokinase activatorsMeihua Tu, Pfizer, USA

Title: Non-competitive regulation of the human proteasome by natural products and natural product inspired scaffoldsJetze J Tepe, Michigan State University, USA

Title: Rational design approaches to find novel ligands targeting the aryl hydrocarbon receptor: successful applications and mechanistic studiesWilliam H Bisson, Oregon State University, USA

Title: Modulations of protein-protein interactions of EGFRs: Structure, inhibition, dynamics and its implications in breast cancerSeetharama D. Satyanarayanajois, University of Louisiana at Monroe, USA

Title: Development of new antibiotics by targeting essential enzymes in bacteria: Structure-based design and simulation studiesConcepción González-Bello, Universidad de Santiago de Compostela, Spain

Title: Design and synthesis of novel pyrimidone analogues as HIV-1 integrase inhibitorsGuisen Zhao, Shandong University, China

Title: Synthesis and anti-candida activity evaluation of new [1,2,4] triazolo[3,4-b][1,3,4] thiadiazinesMashooq Ahmad Bhat, King Saud University, Kingdom of Saudi Arabia

Title: Newer approaches to the discovery of glitazonesPraveen Thaggikuppe Krishnamurthy, JSS College of Pharmacy, India

Session Introduction

MedChem & CADD-2013




Volume 3 Issue 4Med chem 2013ISSN: 2161-0444, Med chem an open access journal

MedChem & CADD-2013October 15-17, 2013

Design and investigation of multivalent ligands for the detection and treatment of diseasesVictor J. HrubyUniversity of Arizona, USA

Development of drugs for the detection and treatment of degenerative diseases such as cancer, prolonged and neuropathic pain, diabetes, etc. has proved to be very difficult. Most current treatments are inadequate, treat mostly symptoms, and have toxicities and development of tolerance that prevent effective long term use. Recent genomic and proteomic studies have shown that in many cases the diseases result from multiple changes in the expressed genome. These findings present opportunities for the development of new approaches to drug design and development. In particular it is possible to design multivalent ligands that can address 2 or more targets for the disease state, all in a single molecule. Depending on the nature of the target, different strategies are required so as to assure that each of the pharmacophores can act at their particular targets (receptor, accepter, enzyme, etc.) without interfering with the actions of the other pharmacophore. We illustrate these principles and this new approach for two different diseases. In the first case, we address the problem for designing ligands which can treat the most ubiquitous disease in the world, prolonged and neuropathic pain, without toxic side effects, for which there is no current effective treatment. We have designed bivalent and trivalent ligands that can act as antagonists at neurokinin-1 or bradykinin receptors and/or as agonists at the mu and delta opioid receptors in a single molecule. We can demonstrate that these ligands can treat neuropathic pain in vivo without toxicities or development of tolerance. In another example, we demonstrate the development of novel multivalent scaffolds that can target cancer cells but not normal cells, and thus can be used for the early detection and treatment of cancer.

Victor J. Hruby, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyVictor J. Hruby is a Regents Professor in the Department of Chemistry and Biochemistry at the University of Arizona. He received his Ph.D. at Cornell University in Theoretical Organic Chemistry and did a Postdoctoral studies with Nobel Laureate Vincent du Vigneaud. He has been a Pprofessor at University of Arizona since 1968 where he has joint appointments in the Neuroscience Program, Medical Pharmacology, and Bio5 among others. His research interests are in the chemistry, biophysics, molecular pharmacology, molecular biology of peptide hormones and neurotransmitters and their receptors, transduction systems and in the design, synthesis and bio evaluation of novel ligands for the treatment of degenerative diseases.






Structure-based drug discovery for gpcrs: From receptors to ligandsAlexander Heifetz and Richard LawEvotec (UK) Ltd., United Kingdom

G-Protein coupled receptors (GPCRs) have enormous physiological and biomedical importance, being the primary target of a large number of modern drugs. The availability of structural information on the binding site of the targeted GPCR plays a key role in rationalization, efficiency and cost-effectiveness of the drug discovery process. X-ray crystallography, a traditional source of structural information, is not currently feasible for every GPCR or GPCR-ligand complex. This situation significantly limits the ability of crystallography to impact the drug discovery process for GPCR targets in “real-time” and hence there is an urgent need for other practical alternatives. The goal of our research is the generation of GPCR 3D structures by applying integrated experimental-computational methods followed by their application in structure-based drug discovery. This research is done in collaboration with membrane protein molecular dynamics group lead by Dr. Philip Biggin from University of Oxford, UK and Structural-Biology group for membrane proteins lead by Prof. So Iwata from Imperial College London, UK. The research is supported by Royal Society UK and Evotec Ltd. The experimental validation of this research is provided mainly by Evotec within real drug discovery projects. The results of this research will be exemplified by MCH-1R, Orexin-1 and -2 Receptors, 5HT2c and/or other drug-discovery cases.

Alexander Heifetz et al., Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyAlexander Heifetz is a principal scientist at Evotec (UK) Ltd, a drug discovery services company. He provides CADD expert support for drug discovery programs. He obtained his Ph.D. from the Weizmann Institute of Science, Israel, in 2001 under supervision of former Israeli president and Foreign Member of the Royal Society Prof. Ephraim Katzir and Dr. Miriam Eisenstein. He has more than 12 years of experience in drug discovery industry (EPIX Pharmaceuticals and Evotec) and was involved in discovery of 3 clinical drug candidates for treatment of anxiety, major depressive disorder, pulmonary hypertension, and Alzheimer’s disease. He has more than 18 patents, patent applications and a wide range of publications in the area of medicinal chemistry and molecular modelling. Recently, he received the Royal Society Industry Award and established collaboration with academic group of Dr. Phillip Biggin from the University of Oxford, for development of methods for GPCR modelling.






DNA-Binding polyamides designed against E1, E2 binding sites of HPV DNA show dramatic anti-HPV activity in cell and tissue cultureJames K. BashkinNanoVir, USA

A series of polyamides based on pyrrole-imidazole polyamides was designed to interfere with viral protein-viral DNA interactions at the origin of replication of the high risk human papillomavirus types 16, 18 and 31. The specific sites targeted were the E1 and E2 protein binding sites on the viral genomes. The initial library showed hits in cell culture screens. Activity was assessed by qPCR determination of viral DNA 48 h after treatment in cell culture. Dose response curves were determined in all cases, with at least triplicate points. Active compounds were further elaborated and modified in a series of subsequent libraries, with initial optimization achieving many sub-100 nM IC50s and apparent IC50’s as low as 36 nM. Since the three viral genomes are not degenerate for polyamide binding in the target regions, we were surprised to find that a significant number of compounds showed broad-spectrum anti-HPV activity against all three viral subtypes investigated (16, 18 and 31). Although the MWs are high, excellent cell culture activity is seen, in agreement with related studies. Two compounds are in preclinical development and have been scaled up to >6 g. More recently, we have discovered a new class of polyamides functionalized at the N-terminus which are active to IC50s of ca. 10 nM. Most recently, important clues to the mechanism of action have been discovered: HPV-infected cells treated with active compounds show activation of one branch of the DNA Damage Response Pathway, while uninfected cells show no such response.

James K. Bashkin, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyJames K. Bashkin completed his D.Phil. at the age of 24 years from the University of Oxford (U.K.) and postdoctoral studies from Harvard University. He is co-founder and director of chemistry at NanoVir LLC and Professor of Chemistry & Biochemistry at the University of Missouri-St. Louis. He has published more than 60 papers, has 11 issued U.S. patents, and serves as an editorial advisory board member of Chemical Reviews.






Structure-guided design, synthesis, and evaluation of guanine-derived inhibitors of the eIF4E mRNA-cap interactionXiaoqi ChenAmgen, USA

Xiaoqi Chen, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds displaying potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC50 of 2.5 M for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point towards the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.

HN

N N

N

O

NH

OCl

MeP

O

OHOH

HN

N N

N+O

H2N

O

HO OH

P-OO

O-O

m7-GMP, eIF4E SPA IC50=14∝M 33, eIF4E SPA IC50=95nM






The design and discovery of CXCR4 chemokine receptor antagonists through incorporation of GPCR-medchem based fragmentsLarry WilsonEmory University and Emory Institute for Drug Development, USA

In the world of G-protein coupled receptor drug research, there have been many profitable developments leading to historical and recent therapeutic breakthroughs. The chemokine receptors are a newer addition to the list of the growing number considered as GPCR “druggable” targets with two drugs now approved in this area. Our interest in the chemokine receptor CXCR4 comes from the involvement of this GPCR in immune system complex functions. Designing antagonists of this receptor would result in potential drugs for treatments varying from stem cell mobilization to prevention of HIV virus entry and infection. The recent drug approval of the cyclam AMD3100 illustrates the potential. Our effortts involve the design of new ligands of the CXCR4 receptor based on fragments and chemotypes in a de novo hit-to-lead effort. These fragments were selected based on their frequency of appearance in medicinal chemistry and GPCR small molecule research. This has resulted in the discovery of CXCR4 antagonists containing the tetrahydro-isoquinoline (TIC) and piperazine fragments, which possess nanomolar potencies against the receptor in various bioassays of ligand (SDF-1/HIV) and receptor (CXCR4) involvement. The strategy and design along with the synthesis and biological results will be presented. Also, some computational modeling showing proposed binding modes of these molecules and the CXCR4 receptor will be shown.

Larry Wilson, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyLarry Wilson completed his Ph.D. from Emory University and postdoctoral studies from Stanford University. He has served various roles in research and development groups at several large pharmaceutical and small biotech companies. He has over 50 publications, patents, and review articles. He is currently principal scientist at Emory University, where he serves as project leader of the discovery of CXCR4 antagonists for potential treatments in stem cell mobilization, cancer, and HIV infection.






Understanding the essential requirements for success in structure-based designGregory L. WarrenOpen Eye Scientific Software, USA

We know that for any prediction the quality of the data used to build a model has a direct impact on the quality of the predictions from that model. Developing and validating software for modeling protein-ligand interactions requires protein-ligand structure data; developing and validating high quality software for modeling protein-ligand interactions therefore requires high quality structure data. If predictions from a molecular docking program fail, is the failure the result of poorly developed software, using poor data for the prediction, or the use of poor data invalidation? This presentation will discuss methods to measure the suitability of protein-ligand structure data for docking software validation. Using the recently published iridium data set, it will be shown that a high proportion of structures used for validating docking software in the past are, in fact, entirely unsuitable for this task, but heuristics will be presented that will allow assembly of datasets appropriate for this purpose.

Gregory L. Warren, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyGregory L. Warren received his Ph.D. in Biochemistry from Massachusetts Institute of Technology, Cambridge, MA. He worked as a postdoctoral fellow at Yale Univeristy in the laboratory of Axel Brunger as part of the development team for the Crystallography & NMR System (CNS) refinement suite. He worked for 8 years as a molecular modeler at Glaxo Smith Kline Pharmaceuticals before moving to Open Eye Scientific Software, Inc., where his work currently includes structure based designand X-ray crystallography applications.






Site identification by ligand competitive saturation (SILCS): Computational approach for the identification and optimization of ligands targeting proteins, RNA and other macromoleculesAlexander D. MacKerellUniversity of Maryland, USA

Computational ligand design and optimization typically involve a single binding site, single ligand approach that is time and resource expensive. Fragment-based methods partially overcome this limitation, but current approaches include approximations with respect to the treatment of solvation and protein flexibility. To overcome these limitations we have developed the site identification by ligand competitive Saturation (SILCS) approach that uses explicit solvent all-atom molecular dynamics simulations to identify binding sites on protein surfaces for functional group classes based on rigorous free energy criteria that include protein flexibility and fragment desolvation. Information from the SILCS approach, termed Frag Maps, are produced in an upfront pre-computed calculation that may be rapidly accessed for the identification of novel ligands that bind to the target macromolecule, for de novo ligand design or for ligand optimization. Visualization of SILCS Frag Maps allows for qualitative ligand design by medicinal chemists while the Frag Maps also may be used for rapid, quantitative estimates of relative free energies of binding. Notably, the SILCS methodology may be applied to occluded binding sites such as those present in G-protein coupled receptors (GPCRs).

Alexander D. MacKerell, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyAlex D. MacKerell received a Ph.D. in Biochemistry in 1985 from Rutgers University, which was followed by postdoctoral fellowships in the Department of Medical Biophysics, Karolinska Institutet, Stockholm, Sweden and the Department of Chemistry, Harvard University. In 1992 he acquired his faculty position in the School of Pharmacy, University of Maryland where he is currently the Grollman-Glick Professor of Pharmaceutical Sciences and the Director of University of Maryland Computer-Aided Drug Design Center.






Computer-aided design of glucokinase activatorsMeihua TuPfizer Worldwide Research and Development, USA

Glucokinase (GK), also termed as hexokinase IV, is a unique isoform of the hexokinase enzymes. It catalyzes the phosphorylation of glucose to glucose-6-phosphate. GK plays an important role in the control of whole-body glucose homeostasis by enhancing glucose stimulated insulin release from the pancreatic b-cells and promoting glycogen synthesis in the liver. Compounds that activate GK have been shown to increase hepatic glucose uptake and reduce hyperglycemia in multiple animal models of T2D. Multiple glucokinase activators (GKAs) have been evaluated in the clinic for the treatment of T2D.

However, despite the promising efficacy of this mechanism, there has been significant attrition in the clinical development of glucokinase activators, driven by narrow therapeutic windows against hypoglycemia as well as concerns around durability and chemotype-specific safety issues. These issues with early activators have fostered investigations into structurally diverse second generation activators with different biochemical profile to reduce hypoglycemia risk.

Unlike traditional medicinal chemistry binding affinity optimization, enzymatic biochemical profile (Km and Vmax) has been proved to be extremely hard to SAR. In the talk, we will present a computational model that enabled us prospectively design GKAs with desired biochemical profiles that demonstrated reduced hypoglycemia risk.

Meihua Tu, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]






Non-competitive regulation of the human proteasome by natural products and natural product inspired scaffoldsJetze J. TepeMichigan State University, USA

Multiple myeloma (MM) is an incurable and fatal type of cancer that affects plasma cells, which will accumulate in the bone marrow leading to bone destruction. Although the leading MM drug, bortezomib, is undoubtedly one of the biggest breakthroughs in this field, nearly all patients will become intolerant or resistant within a few years, after which the average survival time is less than one year. The underlining mechanism of resistance to bortezomib has been attributed, in part, to the formation of clusters of mutations in the proteasomes 5 subunit, which prevent drug binding. Unfortunately, since all clinically and second generation proteasome inhibitors proceed via the same mechanism of binding, all of them exhibit high cross-resistance. Thus, proteasome inhibitors that proceed via a different mechanism of action are desperately needed.

We will present the total synthesis and biological activity of several natural products and natural product-inspired scaffolds as mechanistically distinct proteasome inhibitors. The heterocyclic, small molecule proteasome inhibitors regulate proteasome activity via a non-competitive mechanism, by binding in a site not previously targeted by any drugs. These non-competitive modulators acts additively with and overcome resistance to classic MM drugs such as bortezomib. The cellular activity of these orally available small molecules translates well in vivo and delayed tumor growth in an MM xenograft model to a similar extent as bortezomib.

Jetze J. Tepe, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyJetze J. Tepe received his Ph.D. from the University of Virginia in 1998 with Prof. Timothy L. Macdonald and continued his post-doctoral studies with Prof. Robert M. Williams at Colorado State University. In 2000, he joined the faculty at Michigan State University where his lab is focused on the synthesis and biological evaluation of heterocyclic natural products. In 2003, he received the American Cancer Research Scholar award and he was the recipient of the Multiple Myeloma Research Foundation Senior Award in 2008 and 2010 and the International Myeloma Senior Award in 2013.






Rational design approaches to find novel ligands targeting the aryl hydrocarbon receptor: Successful applications and mechanistic studiesWilliam H. BissonOregon State University, USA

The aryl hydrocarbon receptor (AhR) is a ligand activated member of the basic helix-loop-helix (BhLH) family of transcription factors. The AhR is activated by a variety of compounds, both synthetic and natural, including halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and mediates their biological activity. The AhR is a cytosolic transcription factor bound to several co-chaperones. Upon ligand binding, the AhR translocates from the cytoplasm to the nucleus and regulates genes, including several drug metabolizing enzymes that can influence the therapeutic activity of a number of compounds. The AhR regulates proliferation and differentiation of cells. In addition, the AhR induces immunosuppressive regulatory T cells with therapeutic implications in hyperimmune disorders. The role of the AhR has been also studied by us in cancer and in vivo zeebrafish tissue regeneration. Up to now, the AhR-LBD-PASB domain remains experimentally unresolved. Hence, the homology models of the AhR-LBD PASB domain were prepared to identify new AhR ligands by virtual ligand screening. Successful applications in finding novel agonists, selective modulators (sAhRM) and full antagonists of the AhR will be described. Recent mechanistic studies using computational molecular simulations on the AhR models will be reported. The results obtained demonstrate that in the absence of experimentally resolved structures, computational chemogenomics techniques are still a successful tool in the hands of interdisciplinary teams for the discovery of novel AhR-targeted therapeutics.

William H. Bisson, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyWilliam H. Bisson completed his Ph.D in 2003. at Medicinal and Computational Chemistry at the ETH Zurich, Switzerland. In 2004, he joined as a Research Fellow at the Scripps Research Institute in La Jolla, CA. Later in 2006, he started as a Research Associate at the nearby Sanford-Burnham Medical Research Institute. In 2008 he joined as a Research Associate at the Oregon State University and in 2010 he came back to Switzerland, at the University of Geneva as Senior Research Scientist. Currently, he is Assistant Professor at Oregon State University working successfully in inter-disciplinary projects mostly in cancer using computational chemogenomics.






Modulations of protein-protein interactions of EGFRs: Structure, inhibition, dynamics and its implications in breast cancerSeetharama D. SatyanarayanajoisUniversity of Louisiana at Monroe, USA

Proteins interact with each other in a highly specific manner, and these specific interactions play key roles in many cellular processes. In normal life processes, these protein-protein interactions are well coordinated to perform the functions of the cells. Any deregulation of this process can lead to the development of many diseases. HER2, a member of EGFR proteins, is overexpressed in approximately 30% of breast cancers. HER2 is known to form heterodimers with other EGFR proteins such as EGFR and HER3, and is a major therapeutic target in breast cancer treatment. We have designed a number of peptidomimetics to target domain IV of HER2 protein to inhibit HER2-mediated signaling. One of such peptidomimetics, compound 5, exhibited antiproliferative activity with IC50 values in the nanomolar range against HER2 overexpressing breast cancer cell lines SKBR-3 and BT-474. To further investigate the structure-activity relationship of peptidomimetics several analogs were designed. Some of these analogs exhibited antiproliferative activity against breast cancer cell lines in nanomolar concentration. Path Hunter and proximity ligation assay results indicated the inhibition of HER2 heterodimerization by these compounds. Furthermore, in vivo studies in xenograft model of breast cancer suggested that these compounds delayed the breast tumor growth. Compound 5 was conjugated with BODIPY fluorescent probe to evaluate the binding and internalization of 5. These results suggest that small peptidomimetic molecules can inhibit protein-protein interactions of EGFRs, which can be therapeutically useful for controlling breast cancer.

Seetharama D. Satyanarayanajois, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographySeetharama D. Satyanarayanajois is an Associate Professor in the department of basic pharmaceutical sciences, college of pharmacy, University of Louisiana at Monroe. He obtained his Ph.D. degree in the molecular biophysics unit at the Indian Institute of Science, Bangalore, India. During the past several years, he has worked extensively on the design of peptide/peptidomimetic molecules to target proteins that are important in human diseases using computational and experimental techniques. He is the author and co-author of more than sixty publications. He has edited a special series in Methods in Molecular Biology, Drug Design and Discovery -Methods and Protocols.






Development of new antibiotics by targeting essential enzymes in bacteria: Structure-based design and simulation studiesConcepcion Gonzalez-BelloUniversity of Louisiana at Monroe, USA

The possible development of new antibiotics whose mode of action is based on the selective and effective inhibition of an essential route in bacteria that does not have any counterpart in human cells, the shikimic acid pathway, will be discussed. In particular, the talk will be focused in the inhibition of the third and the fifth enzyme of this pathway, type II dehydroquinase and shikimate kinase. Both enzymes are essential in certain pathogenic microorganisms, such as Mycobacterium tuberculosis and Helicobacter pylori, which are responsible for tuberculosis and stomach cancer, respectively. The key interactions of the substrate and product binding and the enzyme movements that are essential for catalytic turnover of both enzymes have been investigated by structural and computational studies. Based on the mode of action of the enzyme, molecular modeling, dynamic simulations and structural studies and by creating favorable interactions with key residues in the enzymatic mechanism several potent inhibitors were designed and identified. Some of them are analogues of the natural substrate, and the others are mimics of the enzyme reaction intermediate.The crystal structures of enzyme/inhibitors complexes reveal an important change in the conformation and flexibility of the loop that closes over substrate binding. Our results on this project will be presented.

Concepcion Gonzalez-Bello, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyConcepcion Gonzalez-Bello has obtained her Ph.D. at the University of Santiago de Compostela (USC, Spain) in 1994. She did two predoctoral stays in the University of Gent (Belgium) with Prof. Vandewalle and in the Scripps Research Institute (USA) with Prof. Nicolaou. After three years of postdoctoral stay in the University of Cambridge (UK) with Prof. Chris Abell, she joined USC as an Assistant Professor, and was promoted to Associate Professor in 2003 and obtained the Spanish habilitation to full Professor in 2011. She is a member of the ChemMedChem International Advisory Board and has published about 50 papers in reputed journals.






Design and synthesis of novel pyrimidone analogues as HIV-1 integrase inhibitorsGuisen Zhao1, Shenghui Yu1, Tino Wilson Sanchez2 and Nouri Neamati21Shandong University, China2University of Southern California, USA

A series of novel pyrimidone analogues have been designed and synthesized as HIV-1 integrase (IN) inhibitors. This study demonstrated that introducing a substituent in the N1-position of the pyrimidone scaffold does not significantly influence IN inhibitory activity. Molecular docking studies showed these compounds could occupy the IN active site and form pi-pi interactions with viral DNA nucleotides DC16 and DA17 to displace reactive viral DNA 3'OH and block intasome activity.Keywords: HIV-1, Integrase inhibitors, Pyrimidone analogues.

Guisen Zhao et al., Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]






Synthesis and anti-candida activity evaluation of new [1,2,4] triazolo[3,4-b][1,3,4] thiadiazinesMashooq Ahmad BhatKing Saud University, Kingdom of Saudi Arabia

Candida species have emerged as the most common cause of systemic fungal infections worldwide over the last two decades. 1,2,4 - triazole moieties have been incorporated into a wide variety of therapeutically interesting drug candidates and antimycotic ones such as fluconazole, itraconazole and voriconazole. The mercapto and thione substituted 1,2,4- triazol ring system have been reported to possess a variety of biological activities such as antibacterial , antifungal, anti-tubercular, anticancer, diuretic and hypoglycemic. The recent literature survey revealed that a special attention was given to those incorporating N-C-S linkage as in the skeleton of the 1,2,4 -triazolo[3,4-b][1,3, 4]thiadiazine derivatives, which proved to have promising biological activities such as antiviral, anti-HIV, CNS stimulant and antifungal. Studies have also confirmed that triazolothiadiazine derivatives possess anti-Candidal activity. Designing new drugs is based on development of hybrid molecules by combining different pharmacophore fragments in a single structure, which may lead to compounds with interesting biological activities. Herein we describe the synthesis of new triazolothiadiazine derivatives, which were tested, in vitro against eleven species. Treatment of 1,2,4-triazole-5-thione derivative 3 with hydrazonoyl chlorides (4a-h) in refluxing ethanol, in the presence of triethylamine, afforded compounds identified as (7Z) -7-[2-substituted phenyl hydrazinylidene] - 6-methyl -3- (pyridine - 4 -yl) -7H-[1,2,4] triazolo[3,4-b][1,3, 4] thiadiazines (5a-h). All compounds were tested in vitro against eleven Candida species and compared with itraconazole. Among these compounds 5a, 5c, 5e and 5g exhibit the highest inhibitory activity against the Candida species at 6.25 µg/ml. This outcome confirms that phenyl, p- methoxy, p-chloro and p-sulfonamido phenyl groups on triazolothiadiazine ring may have a considerable effect on antifungal activity against Candida species. The compounds with p-bromophenyl (5d) and p-flourophenyl (5f) substituents exhibit inhibitory activity against Candida species at 12.5 µg/ml. The compounds with ortho methyl and p-methyl phenyl substituents were devoid of activity upto 100 µg/ml.

Mashooq Ahmad Bhat, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyMashooq Ahmad Bhat has completed his Ph.D. from Hamdard University, New Delhi, India in 2008. Currently he is working as Assistant professor in College of Pharmacy, King Saud University, Riyadh, KSA. He has published more than 25 papers in journals of international repute. He is serving as reviewer of many reputed journals of medicinal chemistry. His area of research is structure based drug design as anticonvulsants and anti-tubercular agents. He has published many single crystal X-ray reports of the synthesized compounds.






Newer approaches to the discovery of glitazonesPraveen Thaggikuppe KrishnamurthyJSS College of Pharmacy, India

Thiazolidines (TZDs) or glitazones are one of the important classes of insulin sensitizers used in the management of type 2 diabetes mellitus. These agents, however, suffer from some serious side effects such as fluid retention, weight gain, congestive heart failure, bone fracture and possibly bladder cancer, which resulted in their withdrawal from clinical use. The TZDs that were withdrawn from the clinical use were developed at the time when enough scientific data were not available on the structure and the transcriptional mechanisms of peroxisome proliferator activated receptors (PPARs). Recent advances in the understanding of structure and function of PPARs, however, has led to more rationalized approaches to develop these agents. This presentation discusses the various approaches that have been made to develop newer glitazones devoid of the problems associated with current TZDs. These approaches are based on the structural considerations of both the ligands and the receptors and also on the profile alterations of the ligands.

Praveen Thaggikuppe Krishnamurthy, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

2: Computer-Aided Drug Design and Structure Determination

Track 2Day 1 October 15, 2013

Session ChairIstvan J. EnyedyBiogen Idec, USA

Session Co-ChairNicolas MoitessierMcGill University, Canada

Title: New approaches to “Hit” optimizationIstvan J. Enyedy, Biogen Idec, USA

Title: Accurate binding site models can be derived from low quality PDB files using an empirical geometry based force fieldColin McMartin, Thistlesoft, USA

Title: Integrating computational approaches into high throughput screening for rational drug discoveryXin hu, National Center for Advancing Translational Sciences, National Institutes of Health, USA

Title: Using side-chain models derived from atomic resolution X-ray crystallography to develop force fields which can predict global energy minimum geometriesRegine S. Bohacek, BostondeNovo, USA

Title: Forecaster: A computational tool for drug design and discovery developed by experimentalists for experimentalistsNicolas Moitessier, McGill University, Canada

Title: Genes to Leads: A rational structure guided lead discovery technology that works for both enzymes and protein-protein interaction targetsKal Ramnarayan, Sapient Discovery, LLC, USA

Title: Discovery of highly-potent and selective inhibitors for the ABCG2 transporterAchene Boumedjel, Université Joseph Fourier de Grenoble, France

Title: Predictive application of bioisostere transformations to identify novel high quality compound ideasMatthew Segall, Optibrium Ltd., UK

Title: Novel sildenafil analogues: Possible drugs for increased sensitivity to chemotherapeutic agentsAina Westrheim Ravna, University of Tromso, Norway

Title: Structural insights of SIR2 proteins from T. cruzi as promising targets to fight against Chagas diseaseAlessandra Nurisso, University of Geneva-University of Lausanne, Switzerland

Title: Stratification of surface lysine residues of bovine testicular hyaluronidase on the base of its 3D structure model: Computer aided drug designing of chondroitin sulphate modified enzyme derivativeAlexander V. Maksimenko, Institute of Experimental Cardiology, Russia


MedChem & CADD-2013






New approaches to “hit” optimizationIstvan J. EnyedyBiogen Idec, USA

Target structure-based “hit” optimization in a drug discovery project is challenging from the computational point of view. Scoring functions cannot predict binding affinity, thus computational chemists must use their intuition or prior knowledge about the target class to prioritize compounds for synthesis. As the pharmaceutical industry targets novel protein classes, computational chemists must use software to build their know-how about the protein. The talk will focus on how we can use solvent mapping and information from co-crystal structures in guiding docking and scoring. Test results of this procedure on seven kinases using the HYBRID docking protocol from Open Eye will be shown.

Istvan J. Enyedy, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyIstvan J. Enyedy has been involved in new target evaluation, hit finding, and hit-to-lead optimization projects for several types of target classes using both ligand and structure-based methods since the past 14 years. He is co-author on more than 30 publications and 9 patents/applications. He received his Ph.D. in 1998 at Catholic University of America, Washington DC, and did postdoctoral training in Dr. Shaomeng Wang’s group at Georgetown University Medical Center, Washington DC. Between 2001 and 2008 he worked at Bayer Pharmaceuticals, West Haven CT and Novartis Institutes for Biomedical Research in Cambridge MA. Since August 2008 he has been working at Biogen Idec, in Cambridge MA.






Accurate binding site models can be derived from low quality PDB files using an empirical geometry based force fieldColin McMartin1 and Regine S. Bohacek21Thistlesoft, USA2BostondeNovo, USA

A new geometry force field based on atomic resolution regions PDB structures was recently published 1. The new force field has now been tested in many examples not included in the original study. It is very successful in preserving geometries and computed energies in packed small molecule crystals and in atomic resolution regions of PDB structures. When applied to low quality PDB structures the force field causes small movements of those atoms with high energy features and anomalous geometries. This results in structures with energies and geometries similar to those found at high resolution. In the present work the force field was applied to binding site models selected from the entire resolution range of the PDB. A binding site model consists of a ligand and residues in close contact. Binding site models are selected if all atoms a reported, have unique coordinates, have Boltzmann factors less than 80 A2 and do not have non-bonded clashes. These criteria are clear and easily applied and thousands of models satisfying these criteria have been found. Application of the force field to these models produces optimized models with similar energy and geometry profiles to those found in high resolution X-ray models. This process has provided a large set of consistent binding site models. The set contains many series of models where a unique binding site (100% sequence homology) is complexed with a variety ligands. This data is ideal for a broad empirical study of the effects of ligands on binding site flexibility. Tools for using this data base for exploring binding site flexibility are given in a poster at meeting2.

Colin McMartin et al., Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyColin McMartin owns a computational soft-ware company, FLO/QXP, which specializes in force field development/application. A recent publication based on atomic resolution protein crystal geometries describes a new geometry force field as well as methods for developing complete models with explicit water and hydrogen bond networks suitable for structure based design.






Integrating computational approaches into high throughput screening for rational drug discoveryXin HuNational Institutes of Health, USA

High-throughput screening (HTS) and structure/ligand-based virtual screening (VS) are two well-established techniques that are widely used in drug discovery. Progress on the applications of virtual and biological screening is currently moving towards the integration of these two synergistic approaches. Given the fact that more than 86% of the molecular targets in Pub Chem have related structural information in PDB, it is expected that a combined campaign with HTS and VS can be conducted in parallel to maximize their output and greatly improve the screening efficiency. Various computational approaches have been introduced to foster the screening process and data integration; however, it remains a challenging task to integrate these two distinct approaches efficiently in practice. Here we present case studies in finding small molecule inhibitors of bacterial virulence effectors combining HTS and computational approaches including molecular modeling and binding-site predication, ligand-based QSAR and pharmacophore search, structure-based docking and virtual screening, MD simulation and binding free energy calculations, and ADME/T modeling. To facilitate the comparative analysis and visualization of VS and HTS data, we developed a web-based tool that integrates the rich biochemical assay data of HTS, 3D structures of protein targets, and predicted protein-ligand binding models from VS into a unified system for efficient data mining. A user-friendly graphical user interface allows users to visualize and manipulate the multidimensional data in an interactive environment, providing a useful informatics platform for computer-aided rational drug discovery.

Xin Hu, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyXin Hu received his B.S. in Pharmacy in 1991 from Beijing University, Ph.D. in Pharmaceutical Sciences in 2003 from North Dakota State University, followed by a postdoctoral training at The Rockefeller University. Currently, he is a research scientist at the National Center for Advancing Translational Sciences, National Institutes of Health (NCATS/NIH).






Using side-chain models derived from atomic resolution X-ray crystallography to develop force fields which can predict global energy minimum geometriesRegine S. Bohacek1 and McMartin C21BostondeNovo, USA2Thistlesoft, USA

Prediction of low energy conformers in a protein is a challenging computational problem because the energy depends on a large number of intermolecular interactions. Each conformer will experience a very different set of interactions and the energies of these must be determined accurately to find a minimum. The energies depend on the accuracy of the geometry and the competence of the mathematical modeling of potential energy. To learn how to compute these energies, we are exploring energy functions using a large set of models of amino acids models with diverse contact shells. The models are derived from atomic resolution protein crystallography and are extremely accurate. The initial test set consists of models of amino acids plus neighboring residues. Conformers are generated using a modified allegrow. These are tested using energy minimization using an empirical geometry optimization force field and additional energy terms. Preliminary results show that results for polar side-chains depend on the solvation state. Published methods for adding explicit solvent and creating optimum hydrogen bonding networks to each conformational model are being tested.

Regine S. Bohacek et al., Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyRegine S. Bohacek is founder and owner of Boston Denovo.com and has published extensively in the field of computational chemistry with a particular interest in de novo methods and structure based design






Forecaster: A computational tool for drug design and discovery developed by experimentalists for experimentalistsNicolas MoitessierMcGill University, Canada

Over the last ten years we have been developing software for drug design and discovery. In order to make them available to experimentalists, efforts were made to automate the processes, thus reducing errors and the need for extensive training. Thus each individual piece of software, including FITTED; a docking program which considers displaceable water molecules, protein flexibility and covalent binding, IMPACTS; a program for prediction of sites of metabolism of drugs and REACT; a tool for virtual combinatorial chemistry have been integrated into a web-based plateform FORECASTER. This platform has then been applied to real case studies. We will present the development of this computational package as well as existing experimental applications and validation. Among these applications are the computer-aided design and synthesis of prolyl oligopeptidase inhibitors that demonstrated high inhibitory potency in cell-based assays and the experimental determination of their major metabolites initially predicted by IMPACTS.

Nicolas Moitessier, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyNicolas Moitessier received his Ph.D. from Université Henri Poincaré (Nancy, France). In 1998, he moved to Montréal where he joined Prof. Hanessian group for post doctoral work. In 2001, he moved back to Nancy to start an academic career then back to Montréal in 2003 (McGill University). His current research interests integrate software development, computational chemistry and organic/medicinal chemistry. He has published over 55 papers and has founded Molecular Forecaster in 2010. In 2008, he received the first Reginald Fessenden Professorship in innovation for the development of the Forecaster drug discovery platform. In 2009, he was awarded the Astra Zeneca Award in Chemistry.






Genes to leads: A rational structure guided lead discovery technology that works for both enzymes and protein-protein interaction targetsKal RamnarayanSapient Discovery, LLC., USA

The entire life sciences industry is focused on only a few hundred protein targets for drug discovery. There are potentially many more novel targets, not only human proteins but also those present in infectious organisms likely to be relevant targets for important new drugs. 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 HTS screens do not generate significant leads and hence other cost-effective technologies are required to generate novel 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 including targets that are involved in protein-protein interaction. Essential ingredients of the technology are: X-ray crystallography, protein modeling, virtual screening, docking and scoring. In this presentation we would like to discuss our technology with specific application examples in protein-protein interactions.

Kal Ramnarayan, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyKal Ramnarayan is the founder, President, Chief Scientific Officer of Sapient Discovery. Previously, he co-founded Structural Bioinformatics, Inc. and Cengent Therapeutics. Prior to Structural Bioinformatics, Inc., he was head of Computational Chemistry at Immuno Pharmaceutics 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. He holds a Ph.D. in Molecular Biophysics from the Indian Institute of Science, Bangalore and has multiple papers and patents and several other patents pending. He is also co-founder of Focus Synthesis, LLC, in San Diego.






Discovery of highly-potent and selective inhibitors for the ABCG2 transporterAhcène BoumendjelUniversité Joseph Fourier de Grenoble, France

Overexpression of multidrug ABC transporters in cancer cells alters anticancer drugs efficacy by reducing their accumulation in the intracellular compartment. One of the three ABC transporters being largely involved in resistance of cancer cells toward treatments is the breast cancer resistance protein (BCRP/ABCG2). Overcoming multidrug resistance (MDR phenotype) against anticancer drugs is a challenging problem. One of the strategies to overcome MDR can be achieved through effective inhibitors of the multidrug ABC transporters involved in the MDR. In the present communication we will shed light on our recent discovery of highly potent, non-toxic and selective inhibitors of ABCG2 transporter. A special focus will be made on 5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl) ethyl-1-carbonyl)-4H-chromen-4-one, namely MBL-II-141. The latter inhibits ABCG2 with high affinity (IC50=0.11 μM) with very low cytotoxicity, giving a markedly high therapeutic index. MBL-II-141 is highly selective for ABCG2 versus other transporters and constitutes a good candidate for in vivo chemosensitization of tumors. The design, synthesis, in vitro and our latest in vivo studies will be presented.

Ahcene Boumendjel, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]






Predictive application of bioisostere transformations to identify novel high quality compound ideasMatthew Segall1, James Chisholm1, John Barnard2, Julian Hayward2, Edmund Champness1, Chris Leeding1, Hector Garcia1 and Iskander Yusof11Optibrium Ltd., UK2Digital Chemistry Ltd., UK

We will describe how the principle of bioisosterism can be applied, in combination with predictive modelling and multi-parameter optimisation, to quickly search for new, high quality compound ideas and optimisation strategies. Bioisosteres are functional groups which have similar physical or chemical characteristics and hence similar biological effects. The relationships between bioisosteres may be encoded as molecular transformations and automatically applied to new compounds to generate novel compound structures that are likely to preserve the required biological activities. In silico models can be applied to predict the properties of the resulting structures, such as ADME and physicochemical characteristics. These data can, in turn, be integrated using a multi-parameter optimisation approach to prioritise those ideas that are most likely to achieve a required property profile. To illustrate this, we will discuss how the BIOSTER™ database of >20,000 precedented bioisostere transformations and molecular modifications resulting from alternative analogue design techniques has been integrated with the StarDrop™ software. We will describe example applications in drug discovery, including lead hopping and patent protection.

Matthew Segall et al., Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]






Novel sildenafil analogues: Possible drugs for increased sensitivity to chemotherapuetic agents Aina Westrheim RavnaUniversity of Tromso, Norway

The phosphodiesterase 5 (PDE5) inhibitor sildenafil (Viagra ®) also inhibits transport of chemotherapeutic agents out of cancer cells via human ATP-binding cassette (ABC) transporters. Attempts to develop ABCB1 (P-glycoprotein) inhibitors have been ongoing for more than 30 years, but because of toxic effects and lack of desired effect of the compounds, none of these have reached the marked yet. Studies have shown that sildenafil increases the intracellular level of the anticancer agents such as paclitaxel, 5-fluorouracil, methotrexate, cisplatin, oxaliplatin and doxorubicin by inhibiting a variety of ABC transporters (ABCB1, ABCC4, ABCC5 and ABCG2), thereby sensitizing cancer cells to these anticancer agents. Furthermore, it has been shown that several ABC transporters are overexpressed in several types of cancer cells and that sildenafil can inhibit tumor growth without cytotoxic agents present. We have identified sildenafil analogues using virtual ligand screening (VLS) and tested them for ABCC5 transporter efflux using inside-out vesicles (IOV). Seven compounds were more potent than sildenafil, and the two most potent showed K(i) of 50-100 nM. These novel sildenafil analogues may be more effective for inhibiting ABC transporter efflux, and the side effects may be fewer. However, it is still too early to say whether the sildenafil analogues can reverse multidrug resistance mediated by ABC-transport in the clinic, but it appears that such compounds may have the potential to improve the therapeutic results of chemotherapy.

Aina Westrheim Ravna, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyAina Westrheim Ravna has completed her Ph.D. at the age of 31 years from the University of Tromsø and postdoctoral studies from the University of Tromsø, including research stays at the Scripps Research Institute and UCSD, La Jolla, USA. She is currently an Associate Professor at the University of Tromsø. She has more than 30 publications.






Structural insights of SIR2 proteins from T. cruzi as promising targets to fight against Chagas diseaseAlessandra NurissoUniversity of Geneva-University of Lausanne, Switzerland

Trypanosoma cruzi is a protozoan pathogen responsible for Chagas disease. Current therapies rely only on a very limited number of drugs, most of them inadequate because of severe host toxicity or drug-resistance phenomena. In order to find therapeutic alternatives, the identification and the study of new biotargets is highly recommended. Recent findings suggested that the inhibition of the silent-information regulator 2 (SIR2)-like proteins, commonly called sirtuins, can cause kinetoplast alterations and cell cycle arrest of the parasite. Therefore, these parasitic sirtuins have emerged as promising new anti-parasitic targets. In the absence of crystallographic data, reliable homology models of sirtuins SIR2rp1 and SIR2rp3 from T. cruzi have been generated. In silico structural analyses revealed important features for the design of novel and selective candidate drugs. Moreover, a library of phytochemicals with a growth inhibitory activity against T. cruzi has been screened against the modeled sirtuins, highlighting the potential mechanism of action of four trypanocidal natural compounds. Taken together, this information on T. cruzi sirtuins may be useful in the research of novel therapeutic strategies against Chagas disease.

Alessandra Nurisso, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyAlessandra Nurisso graduated from the University of Turin (Italy) with a Master Degree in Industrial Pharmacy in 2006. She then completed her Ph.D. in Structural Biology and Nanobiology from the University of Grenoble (France) as a Marie-Curie fellow. In 2010, she joined the Pharmacochemistry laboratory of the School of Pharmaceutical Sciences of the University of Geneva (Switzerland), working two years as a post-doctoral fellow. She is currently Assistant Lecturer at the School of Pharmaceutical Sciences and also the winner of the Scholarship of Excellence of the University of Geneva (Switzerland), working on inter-disciplinary projects related to epigenetics.






Stratification of surface lysine residues of bovine testicular hyaluronidase on the base of its 3D structure model: Computer aided drug designing of chondroitin sulphate modified enzyme derivativeAlexander V. Maksimenko and Robert S. BeabealashviliInstitute of Experimental Cardiology, Russia

Integrity of vascular wall has been underpinned with double protective layer consisting in endothelial cells and their glycocalyx. The injury of vascular wall begins with endothelial glycocalyx degradation. Besides synthesis de novo, the regulators of glycocalyx state are reactive oxygen species, proteolytic and glycosidase enzymes. The latters determine the catabolism of glycosaminoglycan part of glycocalyx. Obstacles of glycosidase study are dealt with niggardly data about these mammalian biocatalysts, their low concentration in organism, small stability, deficiency of structural information. The obtaining of crystal structure of hyaluronidases helps to overcome the mentioned above hindrances.

We used as archetype of the obtained earlier crystal structure of human hyaluronidase-1 in order to construct 3D model of bovine testicular hyaluronidase (BTH). Superposition of 3D BTH model with 3D structure of human hyaluronidase-1 was quite satisfactory, while with 3D structure of bee venom hyaluronidase had some discrepancies (including the presence of epidermal growth factor-like domain in BTH). The active site of 3D BTH model was indicated as well as sorption complex between BTH and minimal substrate (hyaluronan hexamer) and positions of charged amino acid residues (mainly Lys, Asp, Glu). The surface Lys residues were stratificated according to their access for chemical modification (Lys of first, second, third access level and unproductive residues for Lys modification) due to analysis of Lys microenvironment. The destination of BTH modification is the production of stabilized enzyme forms for medical application. According to experimental results, the covalent complex between BTH and chondroitin sulphate (CHS) is more preferable as compared to complexes with other glycosaminoglycans. CHS modified BTH covalent complexes (BTH-CHS) were constructed in silico with different degree of Lys modification (on the base of 3D BTH model). Moreover, the 3D model of BTH-CHS was constructed with practically full modified/blocked Lys residues. According to experimental data, such BTH-CHS conjugate had molecular mass 180 kDa and more and it was perspective for medical use. From in silico point of view, 140 kDa molecular mass of this conjugate was enough already for fully blockade of Lys residues. The 3D position of CHS chains around BTH globule can be multiform. The fully blockade of surface Lys residues can gain in silico with two CHS chains (m.m. 35-50 kDa) or with one CHS chain (m.m. 120-140 kDa). In latter case, BTH globule is located in CHS coat except two sites only without Lys residues. One of these sites is the area around active site of BTH. Such in silico results are agreed with appreciable remain endoglycosidase activity of BTH (68-78%) after its deep modification by CHS with different molecular mass. The topography of Lys residues stipulates the preservation of substrate access to active site of modified BTH that determines the Lys residue selection for development of modified enzyme derivatives.

Alexander V. Maksimenko et al., Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

3: Quantitative Structure-Activity Relationships4: Drug Development and Delivery System6: Drug Interactions8: Pharmacognosy

Track 3, 4, 6 & 8Day 2 October 16, 2013

Session ChairTatsuya TakagiOsaka University, Japan

Session Co-ChairCesar M. CompadreUniversity of Arkansas for Medical Sciences, USA

Title: In silico screening for anti-HPV agents using docking studiesTatsuya Takagi, Osaka University, Japan

Title: The development of the tocoflexols, a series of novel vitamin E analogues with enhanced bioavailabilityCesar M Compadre, University of Arkansas for Medical Sciences, USA

Title: New polymeric “ruthenium-cyclopentadienyl” complexes for drug delivery in cancer therapyAndreia Valente, Universidade de Lisboa, Portugal

Title: Unraveling the human multidrug resistance p-glycoprotein poly-specificityPierre Falson, Institute of Biology and Chemistry of Proteins, France

Title: PK modulation of haptenylated peptides via non-covalent antibody complexationStefan Dengl, Roche Diagnostics GmbH, Germany

Title: Tumour active plant derived compounds in combination with targeted therapy towards overcoming drug resistance in ovarian cancerFazlul Huq, The University of Sydney, Australia

Title: Designed monofunctional platinums found to have significant antitumor activityLaila Arzuman, The University of Sydney, Australia

Title: A phytochemical and biological investigation of Aloe grandidentata Salm-DyckTaghreed Abdou Ibrahim, King Saud University, Saudi Arabia

Title: Docking guided QSAR study on a series of N-acetamideindolecarboxylic acid derivatives acting as HCV NS 5B polymerase inhibitorsVaishali M. Patil, Bharat Institute of Technology, India


MedChem & CADD-2013






In silico screening for anti-HPV agents using docking studiesTatsuya Takagi and Norihito KawashitaOsaka University, Japan

HPV (human papilloma virus) is known as one of the papillomavirus family which is able to infect humans. For more than 90% of cervical cancer, especially squamous cell carcinoma, HPV infection appears to be a necessary factor. Although HPV vaccination was recommended in almost all developed countries, including JAPAN, very recently, serious adverse events were reported. Thus, anti-HPV agents should be developed in order to prevent many types of cervical cancers. However, since more than 120 types of HPVs have been identified, it is not easy to inhibit the tumor promoting activities of all carcinogenic HPVs.

In this study, we tried to develop HPV E6 protein inhibitors using in silico screening, especially, docking studies. The obtained agents are not for anti-cancer drugs but for in vitro studies which can reveal whether E6 protein inhibitors are capable of suppressing canceration of HPV infected cells. If the inhibitors have such activities, it is not impossible to develop anti-HPV drugs for almost all types of carcinogenic HPVs. We applied two kinds of methods: one is an ordinal in silico screening using docking studies, and the other is a pharmacophore screening plus docking studies using the co-crystal structure of HPV E6 protein and PDZ domain. We obtained some lead chemical structures, which are appeared to be effective for revealing the mechanism of canceration of HPV infected cells, using above two kinds of methods.

Tatsuya Takagi, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyTatsuya Takagi has completed his Ph.D. at the age of 32 years from Osaka University.At that time, he had been a research assistant (this position corresponds to Assistant Professor in the USA) of School of Pharmaceutical Sciences, Osaka University for 5 years. Then, since 1993, he had worked for the Genome Information Research Center, Osaka University as a lecturer until he became a professor of Graduate School of Pharmaceutical Sciences, Osaka University in 1998. He has published more than 100 papers in reputed journals and serving as avice deputy chairman of Division of Structure-Activity Relationship of the Pharmaceutical Society of Japan.






The development of the tocoflexols, a series of novelvitamin E analogues with enhanced bioavailabilityCesar M. CompadreUniversity of Arkansas for Medical Sciences, USA

Vitamin E is composed of two series of closely related compounds, tocopherols and tocotrienols; which show a widely varying degree of biological effectiveness. In recent years, the tocotrienols have gained considerable attention because of their beneficial effects in areas such as radiation protection, cholesterol reduction and cancer treatment and prevention. Unfortunately, the potential of the tocotrienols has been hampered because their very short circulation half-life severely limits their bioavailability.

Using state-of-the-art computational techniques, we have developed the tocoflexols, which are designed to overcome the limitations of the tocotrienols. This was achieved by a novel approach in which we created analogues that more effectively use the natural mechanism of retention of vitamin E components in the body. Specifically this was accomplished by designing compounds that are better accepted by alpha-tocopherol transfer protein, the liver enzyme that controls the circulation levels of vitamin E. By maintaining the bioactivity of the tocotrienols while achieving enhanced bioavailability, these compounds may have a strong potential as therapeutic agents.

Structural modification of drugs to take advantage of endogenous transport systems is a novel and intriguing concept whose potential is just starting to emerge. Successful demonstration of its usefulness in this application is likely to encourage development of similar strategies for the future drug design and development in other areas of biomedical sciences.

Cesar M. Compadre, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyCesar M. Compadre has extensive research experience, on the development of bioactive compounds based on naturally occurring compounds, and on the use of molecular modeling in drug design and structure-activity studies. He has published over papers and over 70 patents related to the development of bioactive compounds, and one FDA approved antimicrobial technology. He has a B.S Pharm degree, and obtained his Ph.D. degree in Medicinal Chemistry and Pharmacognosy, from the University of Illinois at Chicago. He conducted postdoctoral research on structure-activity relationships studies using molecular modeling at the University of Illinois and at Pomona College working with Professor Corwin Hansch. Additionally, he had a sabbatical experience at NASA Ames Research Center in computer modeling. At the University of Arkansas for Medical Sciences he established and directs the molecular modeling facility. He has extensive research collaborations with many scientists locally, nationally and internationally.






New polymeric “ruthenium-cyclopentadienyl” complexes for drug delivery in cancer therapyAndreia Valente1, M. Helena Garcia1, Fernanda Marques2 and Philippe Zinck31Faculdade de Ciências da Universidade de Lisboa, Portugal2Unidade de Ciências Químicas e Radiofarmacêuticas, Portugal3ENSCL, UCCS, CCM, France

Andreia Valente et al., Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyAndreia Valente is graduated in Technological Chemistry from the Faculty of Sciences, University of Lisbon, Portugal. She continued her studies in this institution, where she got her Master degree in Biomedical Inorganic Chemistry. Then, she joined the Unity of Catalysis and Solid State Chemistry at Lille I University, in France, where she obtained her Ph.D. in 2010 in the field of Polymerization Catalysis. Then she joined the Organometallic Group from the Center for Molecular Sciences and Materials at the University of Lisbon where she is now a postdoctoral researcher in the field of polymeric metal complexes for biomedical applications, in cancer therapy.

One of the main problems associated with chemotherapy is the high noxious side effects caused by the lack of selectivity, i.e., the drugs are not specific to the cancer cells. The ideal situation is to achieve a high degree of selectivity where the drug might be only delivered to the tumour without affecting the healthy tissues. In this frame, polymeric metal complexes (PMCs) put forward an important contribution to the drug-delivery research in cancer therapy, using polymers as drug carriers. The great advantage is the easier accumulation of polymers in the cancer cells relatively to single molecules (usual drugs), improving the concentration of the drug and thus its efficiency, which will consequently allow to significantly decrease the side effects.

Here we will present the organocatalyzed synthesis and performances of new PMCs of the general formula [RuArLP]+ (Ar=arene, L=heteroaromatic bidentate macroligand and P=coligand), charged with our new emerging ruthenium compounds already recognized as an efficient cancer cell killers. Importantly, our polymers are designed in order to be guided by specific target vectors to efficiently reach the cancer cells. This feature of our new PMCs can also be the key to overcome the toxic side effects of chemotherapy caused by the existing drugs for chemotherapy. The IC50 values in several cancer cell lines, together with a pH dependent hydrolysis in some cases suggest high potentialities for the application of RuPMCs as new drug delivery systems for RuIICp compounds.

“Rum oiety”

Polymeric Chain

Targeting Biomolecule






Unravelling the human multidrug resistance P-glycoprotein poly-specificityPierre Falson1, Lorena Martinez1, Ophélie Arnaud1, Emilie Henin2, Vincent Chaptal1, RupakDoshi4, HochaoTao3, Michel Tod2, Attilio di Pietro1, Qinghai Zhang3 and Geoffrey Chang41CNRS-Lyon 1 University, France2Ciblage Thérapeutique en Oncologie, France3The Scripps Research Institute, USA4School of Medicine University of California, USA

One main mechanism of drug resistance involves multi-drug efflux pumps which expel drugs out of the cells. How these proteins pump out hundreds of toxins, and among them anticancer drugs, while displaying marked specificities is mysterious. We bring here a molecular basis of this mechanism of poly-specificity, having localized the H- and R-sites of the human P-gp, two main sites by which drugs efflux occurs, here exemplified with Hoechst 33342 and daunorubicin. We achieved this by characterizing in cellulo inhibition mechanisms of the selenohexapeptide inhibitor QZ59 enantiomers, the first compounds ever co-crystallized with the mouse P-gp(2), combining these data with the structural analysis of the conformations recently reported(3).

Results show that the SSS QZ59 enantiomer competitively inhibits Hoechst 33342 and daunorubicin transports, with KI,app of 0.15 and 0.3 µM respectively, 13 and 2 times lower than corresponding Km,app. QZ59-RRR in contrast non-competitively inhibited drugs transport, with a moderate efficacy (KI,app≥1.6 µM) but became competitive towards Hoechst 33342 at high concentrations (KI,app~5 µM). This suggests a positional QZ59 groove drugs transport sites overlap, full for the H-site and partial for the R-site. The latter may share the most embedded QZ59-SSS location as supported by docking analyses.

These results will guide the design of compounds acting at the molecular level to block P-gp-mediated drug efflux with the highest efficiency.

Pierre Falson et al., Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyPierre Falson got his Ph.D. at the Lyon University. He is a CNRS Research Director, enzymologist and membrane proteins biochemist, co-leading the ‘Drug resistance mechanism and modulation’ team in the BMSSI CNRS-UCBL1 research unit. He has published 54 publications, patented 6 inventions and licensed to CALIXAR, a startup which he co-founded. He was awarded in 1991 by the Maurice Nicloux prize from the French Society of Biochemistry and Molecular Biology, in 2010 and 2011 by the “National competition of innovative start-ups” and by the Innovation and Transfer Technology prize from the CNRS.






PK modulation of haptenylated peptides via non-covalent antibody complexationStefan DengRoche Diagnostics GmbH, Germany

We applied noncovalent complexes of digoxigenin (Dig) binding antibodies with digoxigeninylated peptide derivatives to modulate their pharmacokinetic properties. A peptide derivative which activates the Y2R receptor was selectively mono-digoxigeninylated by reacting a NHS-Dig derivative with an ε-amino group of lysine 2. This position tolerates modifications without destroying receptor binding and functionality of the peptide. Rationally designed Dig-peptide derivatives can be loaded onto Dig-binding IgGs in a simple and robust reaction, thereby generating peptide-IgG complexes in a defined two to one molar ratio. This indicates that each antibody arm becomes occupied by one haptenylated peptide. In vitro receptor binding and signaling assays showed that Dig-peptides as well as the peptide-antibody complexes retain better potency than the corresponding pegylated peptides. In vivo analyses revealed prolonged serum half-life of antibody-complexed peptides compared to unmodified peptides. Thus, complexes are of sufficient stability for PK modulation. We observed more prolonged weight reduction in a murine DIO model with antibody-complexed peptides compared to unmodified peptides. We conclude that antibody-hapten complexation can be applied to modulate the PK of haptenylated peptides and in consequence improve the therapeutic efficacy of therapeutic peptides.

Stefan Deng, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]

BiographyStefan Dengl has completed his Ph.D. in 2009 in the laboratory of Prof. Dr. Patrick Cramer at the Genecenter of the Ludwig Maximilians University in Munich. He then joined Roche in Penzberg, Germany, as a postdoctoral fellow working in the field of antibody stability and antibody engineering. Since 2012 he is working as a scientist and expert for biostructure & protein design in pharma research and early development at Roche in Penzberg.






Tumour active plant derived compounds in combination with targeted therapy towards overcoming drug resistance in ovarian cancerFazlul HuqThe University of Sydney, Australia

Whereas platinum resistance is associated with increased expression of anti-apoptotic factors such as NF-kB and AKT, a number of phytochemicals serve to dampen their expressions so that they may act synergistically in combination. In this study we investigated synergism from combination of platinum drugs and a number of tumour active phytochemicals including curcumin, EGCG, thymoquinone, resveratrol and genistein in human ovarian tumour models. Generally sequenced combinations with 2 to 4 h time gap are found to be synergistic whereas the bolus is often antagonistic. The variation in nature of the combined drug action with change in sequence of administration clearly indicates that the action of one drug modulates that of the other. Proteomic studies have identified over thirty proteins that are believed to be associated with platinum resistance in ovarian cancer. They belong to six major groups including cytoskeletal proteins, molecular chaperone and stress related proteins, proteins involved in detoxification and drug resistance, proteins involved in metabolic processes and mRNA processing proteins. Synergistic outcome from combinations of cisplatin with phytochemicals is found to be associated with down-regulation of mRNA processing proteins that play a variety of roles in tumour development and progression, and up-regulate molecular chaperones that are needed for constant surveillance to ensure normal protein homeostasis. Detoxification and drug resistance proteins are found to be up-regulated after treatment with synergistic combinations of Cis with other phytochemicals, indicating that the phytochemicals have served to sensitize resistant A2780cisR cancer cells towards platinum action by targeting various cellular pathways.

Fazlul Huq, Med chem 2013, 3:4http://dx.doi.org/10.4172/2161-0444.S1.007

[email protected]






Designed monofunctional platinums found to have significant antitumor activityLaila ArzumanThe University of Sydney, Australia

Although cisplatin is used in the clinic, its use has also been limited due to the presence of side effects and development of drug resistance. Currently much research efforts are being applied in designing new platinums that would interact with DNA differently than cisplatin. In this study, we designed four new platinum(II) complexes of the form [PtL3Cl]Cl coded as LH1, LH2, LH3 and LH4 where L=3-hydroxy pyridine, imidazole, 8-hydroxy quinoline and benzimidazole respectively. Activity of the compounds against human ovarian cancer cell lines: A2780, A2780cisR and A2780ZD0473R, cell uptake, levels of DNA-binding and nature of interaction with pBR322 plasmid DNA have been determined. In addition, combinations of LH1, LH2, LH3 and LH4 with cisplatin and selected phytochemicals were applied to the ovarian cancer cell lines as a function of concentration and sequence of administration. Although LH1 and LH2 are found to be much less active than cisplatin and result into lower intracellular platinum accumulation than cisplatin, LH3 and LH4 are significantly more active than cisplatin especially against the resistant cell lines. Combinations of LH1, LH2 and LH3 with cisplatin are found additive to synergistic against A2780, A2780cisR and A2780ZD0473R cell lines. When combined with phytochemicals genistein and curcumin, LH3 is found to produce sequenced dependent synergism with the bolus showing the greatest synergism. The results of the study can be seen to illustrate structure activity relationships an

Documents

MedChem & CADD-2013 · 2014. 5. 24. · Page 29 2nd nternationa onference on Medicinal Chemistry Computer Aided Drug Designing October 15-1, 2013 Hampton Inn Tropicana, Las Vegas,