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FUJiFILM LifeSciences

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Bio-IT World

Science AAAS

The Scientist


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Wednesday, June 3

1:10 - 5:00 pm Designing Kinase Inhibitors

1:10 pm Chairperson’s Remarks

David Borhani, Ph.D., D. E. Shaw Research, LLC

1:15 Kino-Pocketome: The Structural Classification and Targeting of Non-Traditional Kinase Binding Sites

Ruben Abagyan, Ph.D, Professor, Department of Molecular Biology The Scripps Research Institute Adjunct Professor, University of California, San Diego, School of Pharmacy

A comprehensive structural set of kinases and their complexes with inhibitors and peptides has been collected and classified in terms of multi-conformational (flexible) pockets of various types. An application of the flexible pocketome approach to kinase modeling, virtual ligand screening and ligand specificity profiling is also presented. We applied the method to two types of pockets, the type II inhibitor binding pocket (the DOLPHIN method) and a pocket at the protein-protein interaction interface exemplified by CK2 alpha/beta interactions.

1:45 Selective Rho Kinase (ROCK) Inhibitors: Design and Synthesis

Hartmut Schirok, Ph.D., Senior Scientist, Bayer Schering Pharma AG

Rho kinase plays a pivotal role in vasoregulation, making it a suitable target for the treatment of hypertension and related disorders. The discovery of Bayer Schering’s azaindole-based ROCK inhibitor will be presented. The structure-activity relationships will be disclosed, elucidated through biochemical, functional, and in vivo assays.

2:15 Aggregating Knowledge to Enhance Kinase Drug Discovery

Natasja Brooijmans, Ph.D., Principal Research Scientist, Pharmaceutical Chemistry, Wyeth

The amount of structural and pharmacological information about kinases and their inhibitors has increased significantly over the years thanks to significant efforts from both public and private institutions. While a number of kinase inhibitors have been approved for use in the clinic, kinases as drug targets still form a significant challenge due to protein flexibility in the kinase catalytic domain and issues with selectivity over related and unrelated kinases. We’ll describe our efforts to take advantage of the aggregate of information that is available to enhance kinase drug discovery efforts. Prospective & retrospective virtual screens utilizing multiple crystal structures will be discussed. In addition, we’ll highlight large-scale ligand-based modeling efforts to extract knowledge hidden in databases such as the GVK biodata database.

2:45 Networking Refreshment Break

3:15 Cross-Docking to CDK2: A Virtual Screening Study

Johannes Voigt, Ph.D., Senior Principal Scientist, Schering-Plough Research Institute

The first part of our comprehensive cross docking study on CDK2 covered the analysis of docking accuracy and score/affinity correlations for a uniform set of 150 CDK2 crystal structures In agreement with previous docking/scoring evaluations, the docking accuracy of Gold and Glide was good, while the score/affinity correlations were not satisfactory. In this study virtual screening for this unique data set was investigated. The following questions were addressed: A) Does virtual screening for this data set work? B) If yes, does it work for the correct reasons? Here it is valuable to have the experimentally determined binding modes of the active ligands. C) What is the best choice of the decoy set, what really is a decoy, and is a decoy set only valid in the context of the active molecules? In comparison to our in-house ligands, the DUD CDK2 data set was used  D) Does combing of docking results from multiple protein structures enhance the performance? E) How do Gold and Glide compare?

3:45 The DFG Motif -- a Protonation-Dependent Conformational Switch in Protein Kinases

Yibing Shan, Ph.D., D.E. Shaw Research, LLC

Conformations of the conserved DFG motif is well known to be crucial for selective binding of many kinase inhibitors—including the cancer drug imatinib. Using long molecular dynamics simulations of the Abl kinase, we visualized the DFG flip in atomic-level detail and formulated an energetic model predicting that protonation of the DFG apspartate controls the flip. Consistent with our model’s predictions, we demonstrated experimentally that the kinetics of imatinib binding to Abl kinase have a pH dependence. Our model suggests a role of the DFG motif as a conformational switch in kinase catalytic cycles. In addition, our experimental results on imatinib suggest a convenient assay to identify DFG-out kinase inhibitors in absence of structural data.

4:15 Panel Discussion: Structuring the Road to Success

4:45 End of Workshop

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