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TUESDAY, APRIL, 27
7:00 am Registration and Morning Coffee
8:00 Chairperson's Opening Remarks
FBDD by NMR and Virtual Docking: Puzzling Approaches to Ligand Discovery
Maurizio Pellecchia, Ph.D., Professor, Burnham Institute for Medical Research
8:50 Novel Heparanase Inhibitors Based on NMR Fragment-Based Strategies
Antonio Pineda-Lucena, Ph.D., Principal Investigator, Structural Biology, Medicinal Chemistry, Centro de Investigación Príncipe Felipe
A combined strategy based on the development of pharmacophore hypotheses and NMR approaches is reported for the identification of novel inhibitors of heparanase, a key enzyme involved in tumor metastasis through the remodeling of the subepithelial and subendothelial basement membranes, resulting in the dissemination of metastatic cancer cells.
9:20 Shortening the Time to a Successful Fragment HTL Campaign
Sandy Farmer, Ph.D., Director, Structural Research, Boehringer Ingelheim Pharmaceuticals, Inc.
The parallel application of multiple fragment screening approaches is shown to yield a natural prioritization of fragment hits whose potential to yield an X-ray co-structure can be further increased by additional and more quantifiable biophysical data. Progression of such fragment hits into X-ray, when coupled with a stringent assessment of chemical tractability, is shown to identify early on the most promising candidates for chemical elaboration. The process of fragment chemical elaboration will itself highlight several key organizational requirements for success.
9:50 Networking Coffee Break
10:15 Methods for Structure Based Scaffold ReplacementSponsored by
Chris Williams, Ph.D., Principal Scientist, Chemical Computing Group
Small molecule scaffold replacement techniques are an important part of drug discovery because of the need to find rapid “follow on” compounds or alternate series. Fragment-based drug discovery techniques also benefit from scaffold replacement methods because of the need to link fragments that bind to a receptor. We present methods for structure-based scaffold replacement that combine techniques from pharmacophore discovery and ligand receptor docking. Strategies for the creation of 3D virtual fragment databases are discussed as well as the results of computational experiments.
10:45 SPR-Based Screening of Fragment Library: Case Studies
Girija Krishnamurthy, Ph.D., Principal Research Scientist, Pfizer, Inc.
Fragment based screening (FBS) entails screening low molecular weight fragments for binding to target proteins. Recently, Surface Plasmon Resonance (SPR) technology has emerged as a powerful tool to identify and investigate the binding interactions of such compounds in the fragment library. The major advantages of the SPR-based approach are reduced protein consumption and the ability to screen out promiscuous hits from fragment library. A library of about 6000 fragments was screened for their ability to bind to carbonic anhydrase and an enzyme target. This presentation will focus on the use of FujiFilm AP-3000 platform in FBS, the results of the screening efforts against Carbonic Anhydrase and a target protein and the follow-up strategy used in lead generation.
11:15 Computational Approaches to Fragment-Based Design and Predicting Fragment PosesSponsored by
Shikha Varma-O’Brien, Ph.D., Director, Life Sciences Modeling & Simulations, Accelrys, Inc.
Fragment-based design methods are increasingly popular as they allow chemists to leverage existing structural, chemistry and reagent information to rapidly design new compounds. This presentation will review some new fragment-based design protocols using proven scientific modeling and simulations tools from Accelrys. The computational methods include pharmacophore and structure-based approaches which can both be used for de novo design of candidates, prediction of fragment binding modes and analysis of active site affinity for various functional groups. Mining experimental data from the PDB in the context of fragment-based design will also be highlighted.
11:30 Exploring Flexible Protein Targets by Fragment-Based Drug Discovery
Peter Brandt, Ph.D., CSO, Beactica
Fragment-based drug discovery and SPR-driven approaches will be exemplified with two flexible drug targets, HIV-1 reverse transcriptase & HCMV protease. The presentation will be focused on screening strategies, methods for fragment triaging, and discovery of novel inhibition mechanisms. Furthermore, implications of ligand-induced protein conformational change on fragment-based approaches will be discussed.
12:00 Using Octet RED384 for Rapid Label-free Screening of Small Molecules and Fragments
John Wang, Ph.D., Scientist, ForteBio, Inc
The Octet RED384 system is becoming a popular choice for label-free screening of drug-like leads from ever larger libraries of small molecule and fragments due to its novel Dip and Read simplicity and other workflow benefits. A technical evaluation of the Octet RED384 system with respect to data quality, detection sensitivity, reliability, throughput and ease-of-use will be presented.
12:15 pm Lunch on Your Own
1:25 Chairperson's Remarks
Cathy Moore, Ph.D., formerly Senior Principal Scientist, Pfizer, Inc.
1:30 Building an FBDD Approach to Rapid Target Validation and Accelerated Path to the Clinic
Dean R. Artis, Ph.D., Senior Vice President, Global Research, Elan Pharmaceuticals
2:00 Fragment Optimization of a Dynamic Target: Finding Non-peptidic Matter for the Ala-Val Subpockets XIAP
Cathy Moore, Ph.D., formerly Senior Principal Scientist, Pfizer, Inc.
Dynamic binding sites pose challenges for identifying fragments that bind. A general approach to stabilizing these sites and its application to finding non-peptidic fragments for the AVPI binding motif of XIAP's BIR3 domain will be presented.
2:30 Fragment-Based Design of Oally Bioavailable CDK Inhibitors
Andrew Woodhead, Ph.D., Associate Director, Medicinal Chemistry, Astex Therapeutics
Astex has previously described the discovery of AT7519 a novel, efficacious CDK inhibitor suitable for intravenous dosing, identified via fragment screening and subsequent structure-based drug design . A brief outline of Astex’s approach to FBDD will be given, followed by the medicinal chemistry strategies we used for developing orally biovavilable compounds. This program led to the discovery of AT9311. AT9311 possesses a differentiated kinase inhibitory profile with respect to AT7519, has good pharmacokinetic properties and efficacy in a mouse tumour model when dosed orally.
3:00 Use of a Metabolome-Inspired Fragment Library for Identifying Startpoints for Anti-Infective DrugsSponsored by
Doug Davies, Senior Director, Emerald BioStuctures
Emerald Biostructures has developed a ~1500 compound fragment library (Fragments of Life™) that incorporates natural metabolites, chemically tractable derivatives of metabolites, and biaryl peptide mimetics. Our library is designed to target active sites, allosteric sites, and potential sites of protein-protein interactions. Fragments of Life™ is being deployed against multiple infectious disease targets in the Seattle Structural Genomics Center for Infectious Disease (www.SSGCID.org), an NIAID-funded initiative to deliver more than 500 new structures in five years. Recent results, including a fragment screen against Influenza A polymerase will be discussed.
3:15 Networking Refreshment Break, Poster and Exhibit Viewing
4:00 Chem_BLAST – A Rule-Based Method to Develop Advanced Structural Ontologies for Fragment-Based Drug Design using the PDB
Talapady Bhat, Ph.D., Project Leader, Biochemical Science Division, NIST
Protein Data Bank and PubChem are the world’s largest collection of 3-D and 2-D structures of interest to Fragment-Based Drug Design. However, users of these must interact with a variety of information standalone applications and ontology to benefit from the existing vast knowledge base such as the PDB. This limitation promotes the need to define and develop rule-based stringent ontology of fragments for information processing and sharing. Automated user-friendly method called Chem-BLAST will be described as a solution with emphasis to diseases such as AIDS, Cancer and Biofuels.
4:30 Fragment-Based Lead Discovery through Chemotype Evolution
Daniel A. Erlanson, Ph.D., CoFounder, Carmot Therapeutics, Inc.
5:00 Talk Title to be Announced
Ravi G. Kurumbail, Ph.D., Research Fellow, Pfizer, Inc.
5:30 Networking Cocktail Reception in the Exhibit Hall
6:30 End of Day
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