SABPA

Advances in Structure-based Drug Design

Science & Technology Forum V --- 2007

March 17th, 2007, Inst. of Americas, UCSD


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8:00 am	Continental Breakfast & Registration
8:30 am	Event Chair's Remarks Rongshi Li, Ph.D . Co-Chair of SABPA Science & Technology Committee Senior Director, HT Medicinal Chemistry, ChemBridge Research Laboratories
8:40 am	Computer-aided Drug Design J. Andrew McCammon, Ph.D. Professor, UCSD
9:20 am	Fragment-Based Discovery of Selective, Orally Bioavailable Tyrosine Kinase Inhibitors for Targeted Treatment of Human Cancers Stephen K. Burley, M.D., D.Phil., F.R.S.C., CSO and Sr. VP, SGX Pharmaceuticals, Inc.
10:00 am	Recent Advances in Structure-based Modeling of GPCRs Using Tools in the Schrodinger Suite Christopher Higgs, Ph.D. Senior Applications Scientist, Schrodinger, Inc .
10:15 am	Coffee break/Exhibit/Networking
10:35 am	Lead Generation Using Fragments and Structures Jeffrey A. Stafford, Ph.D. Vice President of Chemistry, Takeda San Diego
11:15 am	Structure-based design of HCV NS3-4A protease inhibitors Chao Lin, Ph.D. Vertex Pharmaceuticals .
11:55 am	Fragment based flexible ligand docking and screening with eHiTS Darryl Reid, MSc, SimBioSys, Inc.
12:10 pm	Closing Remarks Hui Li, Ph.D. Principal Scientist, Pfizer Global Research La Jolla , President, SABPA San Diego
12:15 pm	Lunch and networking

Abstract

Computer-aided Drug Design

J. Andrew McCammon, Ph.D.

The selective character of the binding and reactivity of key biological molecules is essential for life. Properly understood, such selectivity can be exploited in the design of drugs, novel antibodies or enzymes, sensors, or a host of other materials or devices. This talk will provide a brief overview of how computer simulations can be used quantitatively to interpret the selectivity of molecular behavior. Particular emphasis will be placed on proper accounting of the flexibility of the receptor in the design of ligands. The potential of new generations of computing hardware and methodology to dramatically transform this area of work will be emphasized.

Fragment-Based Discovery of Selective, Orally Bioavailable Tyrosine Kinase Inhibitors for Targeted Treatment of Human Cancers

Stephen K. Burley, M.D., D.Phil., F.R.S.C.

SGX Pharmaceuticals, Inc. (SGX) has developed a fragment based drug discovery platform that utilizes high-throughput X-ray crystallography for lead identification/optimization. The proprietary FAST? (Fragments of Active Structures) process exploits crystallographic screening to detect, visualize, and identify small ligands (MW 150-200) that are bound to the target protein. Each member of the FAST? fragment/scaffold library was selected to be amenable to rapid chemical elaboration at two or three points of chemical diversity using parallel organic synthesis. Initial lead optimization involves using our knowledge of the co-crystal structure of the target-fragment complex and advanced computational chemistry tools to guide synthesis of small focused linear (one-dimensional) libraries. These linearly elaborated fragments/scaffolds are then evaluated with in vitro biochemical and cellular assays and co-crystal structure determinations. Thereafter, optimal variations at each point of chemical diversity are combined to synthesize focused combinatorial (two- or three-dimensional) libraries that are again examined with assays and crystallography. (The potential chemical diversity of the fully elaborated FAST? fragment/scaffold library far exceeds 160 million compounds.) Active compound series are prioritized for further medicinal chemistry and compound development efforts using the results of in vitro and in vivo ADME and in vitro toxicology studies Successful applications of the FAST? fragment-based lead discovery/optimization process will be presented for a portfolio of well validated oncology targets.

Recent Advances in Structure-based Modeling of GPCRs Using Tools in the Schrodinger Suite

Christopher Higgs, Ph.D. Senior Applications Scientist, Schrodinger Inc.

G-protein coupled receptors (GPCR) constitute one of the most important drug target classes in pharmaceutical research. To date only one crystal structure of a GPCR, bovine rhodopsin, has been crystallized and as a result, ligand-based methods have been the primary tool of choice for computational chemists. Homology models of GPCRs can be a useful tool during lead discovery but is often a more effective tool during lead optimization where binding modes based on available SAR data can be hypothesized. At Schrödinger, we are currently developing tools to aid in the construction of GPCR homology models and the current progress will be described.

Lead Generation Using Fragments and Structures

Jeffrey A. Stafford, Ph.D.

Fragment-based drug discovery (FBDD) has emerged as a valuable medicinal chemistry tool for lead generation. When coupled with X-ray crystallography, the technical hurdles faced when addressing a fragment's low binding affinity are balanced with opportunities for creativity and drug specificity. Proteases and kinases are attractive drug targets due to their important roles in disease pathology and their amenability to FBDD and SBDD. This presentation will highlight specific examples of FBDD and SBDD on protease and kinase drug targets.

Structure-based design of HCV NS3-4A protease inhibitors

Chao Lin, Ph.D.

The HCV NS3-4A protease, which is essential for viral replication, is considered one of the most attractive targets for developing novel anti-HCV therapies. However, discovery of potent and selective small-molecule inhibitors of HCV NS3-4A protease as oral drug candidates has been hampered by the shallow substrate-binding groove of the protease. Serine trap warheads have been used to covalently anchor inhibitor scaffolds and to increase their affinity to the protease. For the HCV NS3-4A protease, early generation of aldehyde-based inhibitors evolved into more drug-like ¦Á-ketoamide inhibitors. Kinetic and structural studies of ¦Á-ketoamide inhibitors revealed an unusual mechanism of binding in the catalytic site. Optimization of ¦Á-ketoamide scaffolds led to the discovery of VX 950 or telaprevir, a novel, potent, and selective inhibitor of HCV NS3-4A protease, which is currently in phase 2b trial for hepatitis C.

Fragment based flexible ligand docking and screening with eHiTS

Darryl Reid, MSc SimBioSys, Inc.

The challenge of rational drug discovery often involves combining several different computational methods to help generate and analyze enough information about your system of interest. eHiTS Filter is a ligand based screening tool that uses a surface property based pseudo-pharmacophore to determine molecular similarity. This method has been shown to enrich data sets with molecules that are more likely to bind to target receptors. Used as a pre-screening tool for docking, eHiTS Filter can dramatically reduce the computational time need to screen a full database, while still giving you the docked poses of the most interesting structures. eHiTS is a systematic and exhaustive fragment based docking program that generates very good binding poses for potential ligands. The CheVi visualization package shows the interactions between ligands and receptors in a very unique way which assists in better understanding of the binding at the active site.

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