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TUESDAY, APRIL, 27

7:00 am Registration and Morning Coffee

8:00 Chairperson's Opening Remarks

Fragment – Based Techniques

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 pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:00 Break

APPLIED FBDD – LESSONS LEARNED

1:25 Chairperson's Remarks

1:30 Recent Experiences in Fragment-Based Discovery

Roderick E. Hubbard, Ph.D., Professor, Research, Vernalis, Ltd.

Comparison of methods for detecting fragment binding. New examples of fragment-based discovery. Challenges in the integration of fragments with medicinal chemistry.

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 Speaker to be Announced

4:30 Combining Structurally Related Fragment and Screening Libraries: A Case Study

Daniel Obrecht, Ph.D., CSO, Polyphor Ltd.

Polyphor has developed an integrated drug discovery approach combining a core/scaffold-rich general library with a specially designed, structurally related fragment library. The combination of structural information from fragment hits obtained from screening using SPR techniques, and structural information from related final cpds (protein X-ray where possible), together with computational methods allows for an efficient fragment-to-lead optimization. A case study will highlight the advantages of this approach.

5:00 Talk Title to be Announced

Ye Che, Ph.D. Pfizer, Inc.(invited)

5:30 Networking Cocktail Reception in the Exhibit Hall

6:30 End of Day

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