Thursday, June 24, 2010
8:15 am Registration and Morning Coffee
New Computational Methods in SBDD
8:45 Chairperson’s Remarks
Roderick Hubbard, Ph.D., Professor and Senior Fellow, Structural Sciences, University of York and Vernalis
9:00 An Enriched Structural Kinase Database to Enable Structure-Based Drug Discovery
Natasja Brooijmans, Ph.D., Principal Research Scientist, Computational Chemistry & Cheminformatics, Pfizer, Inc.
A structural database, the Kinase Knowledge Base (KKB) will be presented. It contains all kinase catalytic domain structures, allows kinome-wide structural analyses due to the development of a common numbering scheme, and the ability to perform protein-ligand distance queries. Many of the queries enabled in KKB are not possible or time consuming within the Protein Data Bank framework. Both the development of the database and a number of use cases will be presented. These illustrate the power of a protein-family focused structural database while integrating biological binding data to support structure-based drug design.
Sponsored by9:30 LowModeMD: Conformational Search of Small Molecules, Macrocycles and Protein Loops
Chris Williams, Ph.D., Principal Scientist, Chemical Computing Group
A method for conformational searching based on perturbing existing conformations along a molecular dynamics trajectory with velocities concentrated on low-frequency vibrational modes is presented. The method is efficient for large systems, using only standard forcefield energy and gradient evaluations, along with a novel Chebyshev polynomial to dampen the high-frequency components of randomly generated Maxwell-Boltzmann velocities. The results of several computational experiments suggest that the method is capable of efficiently sampling the low strain energy conformations of systems with complex non-bonded interaction networks such and macrocycles and protein loops.
Sponsored by10:00 Hybrid Docking Mark McGann, Ph.D., Principal Developer, OpenEye
Protein structures are commonly crystallized in the presence of a ligand, but the ligand information is typically discarded by docking programs. Similarly, ligand-based virtual screening methods typically do not make use of protein structure information even when that information is readily available. FRED is a molecular docking program capable of using the structure of a bound ligand, in addition to the structure of the protein, to enhance virtual screening performance. This hybrid approach is shown to be superior to either pure ligand or pure structure based approaches.
10:30 Networking Coffee Break, Poster and Exhibit Viewing
11:00 Chem-BLAST — A Rule-Based Method to Develop Advanced Structural Ontologies for Structure-Based Drug Design
Talapady Bhat, Ph.D., Project leader, Biochemical Science, NIST
Protein Data Bank (PDB) and PubChem are the world’s largest collection of 3-D and 2-D structures of interest to Structure-Based Drug Design and users of these must interact with a variety of information standalone applications and ontology. Rule-based ontology for seamless query and integration of variety of information with Semantic Web concepts will be described and illustrated using a new technology called Chem-BLAST
Sponsored by11:30 Thermodynamic Characterization of Interfacial Water Molecules Involved in Binding Affinity and Specificity
Woody Sherman, Ph.D., Vice President, Applications Science, Schrodinger, Inc.
Explicit water molecules play an integral role in the protein-ligand binding process and a substantial amount of energy can be associated with the displacement or bridging of even a single water molecule by a ligand. In this work, we describe a new method to quantify the thermodynamic properties (entropy and enthalpy) of explicit water molecules in protein binding sites. We present applications of this methodology to a number of pharmaceutically relevant target classes, including kinases, proteases, and GPCRs as well as protein-protein interaction interfaces.
12:00 pm Luncheon Presentation (Sponsorship Opportunity) or Lunch on your Own
(Contact Katelin Fitzgerald at email@example.com or 781.972.5458)
In Silico Discovery of
Small Molecule Binders
1:25 Chairperson’s Remarks
Alan Rigby, Ph.D., Assistant Professor of Medicine, Harvard Medical School; Director, Program in Drug Discovery and Target Validation, Beth Israel Deaconess Medical Center
1:30 In Silico Discovery of Small Molecule Transcription Factor Inhibitors
The ability to selectively target the interaction interface of protein-protein and/or protein-DNA transcriptional complexes offers a unique opportunity to reprogram gene expression programs that are often deregulated in cancer. We have developed and benchmarked a computer aided drug discovery (CADD) platform for evaluating this novel chemical space. I will present SBVS and stringent LBVS scaffold expansion data that builds upon our previous peptidomimetic studies, identifying unique small molecule chemotypes that specifically target these transcription factor-DNA interfaces.
2:00 Structure-Based Investigation of Wnt Signaling Inhibitors
Jie Zheng, Ph.D., Associate Member, Department of Structural Biology, St. Jude Children’s Research Hospital
Wnt signaling plays crucial roles in embryonic development and in tissue maintenance in adults. Abnormal activation of Wnt signaling is observed in several types of cancers. Dishevelled (Dvl) is a key molecule in the Wnt pathways that, through its PDZ domain, relays Wnt signals from membrane-bound Wnt receptors to downstream components. We have worked to develop small-molecule inhibitors of the Dvl PDZ protein–protein interaction for use in the elucidation of biological processes and as potential cancer-treatment and prevention agents.
2:30 A Wish List for Computation, What Does the SBDD Community Want / Need?
Ryan Lilien, Ph.D., M.D., Assistant Professor, Department of Computer Science and Banting & Best Department of Medical Research, Faculty of Medicine, University of Toronto
A significant communications barrier exists between those in the computational and life sciences. As a result, there are many important problems for which a computational solution has never been pursued. We are attempting to bridge this communications gap with a series of conference sessions and special events. We are soliciting a "wish list" of open computational problems that are most important to SBDD researchers. Where does the computational community need to focus their efforts?
2:45 Networking Refreshment Break, Poster and Exhibit Viewing
3:30 Docking-Based Virtual Screenings for GPCR Ligands: Area of Applicability and Strategies for Optimization
Stefano Costanzi, Ph.D., Head of the Molecular Modeling Unit, Laboratory Biological Modeling, NIDDK, National Institutes of Health
Using the ß2-adrenergic receptor as a case study, we have investigated the applicability of docking-based virtual screening to G protein-coupled receptors (GPCRs). When applied to the crystal structure, the screening yielded a remarkable prioritization of a pool of known binders dispersed within a large set of decoy compounds. The retrieval yield can be further improved by generating an ensemble of alternative conformations of the receptor that accounts for its flexibility. Moreover, the screening can be biased toward the retrieval of agonists or blockers through the use of structures previously optimized around a docked ligand. Notably, our docking-based virtual screening experiments proved to be very effective with the experimental structure of the receptor, but also with homology models of different levels of accuracy, suggesting their general applicability to the identification of GPCR ligands.
4:00 Mutation Data Driven Binding Modes for CCR5 Antagonists: Applications in Structure Based Design
Rama Kondru, Ph.D., Principal Research Scientist, Discovery Chemistry, Hoffmann-La Roche
The CC chemokine receptor CCR5 is a co-receptor for macrophage tropic human immunodeficiency virus type I (HIV-1). Hence, one of the most promising approaches to block HIV-1 entry is to use small molecule antagonists for CCR5. Presently, Maraviroc from Pfizer is a marketed drug; and other compounds like Vicriviroc and Aplaviroc from Schering and GSK respectively have also gone through clinical trials for HIV. To facilitate development of next generation antagonists for HIV-1, we explored how the above mentioned compounds antagonize CCR5 by mapping their binding site using site directed mutagenesis and receptor protein modeling. The fully mapped binding pocket for CCR5 was used as a structure based design tool for lead optimization for the in-house compounds.
4:30 An Analysis of the Binding Efficiencies of Drugs and Their Leads in Successful Drug Discovery Programs
Emanuele Perola, Ph.D., Research Fellow, Computational Drug Discovery Technologies, Vertex Pharmaceuticals, Inc.
The concept of binding efficiency was introduced to help optimize the balance of molecular weight and potency in drug discovery programs. However, clear guidelines on how to use this parameter have yet to be established. To this end a dataset of 60 pairs of approved drugs and corresponding leads with known binding affinities was generated and the binding efficiency trends were analyzed. The results of this analysis and the potential impact of the emerging trends on lead selection and optimization strategies will be presented and discussed.
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