GPCR-Based Drug Design

Computational and Structural Approaches

April 17-18, 2013

The past few years have witnessed an increased pace of reports on different G protein coupled receptors or GPCR-ligand pairs whose crystal structures have been elucidated. How can this new structural information be harnessed for drug development against one of the most medically important but difficult to work with class of targets? This inaugural day and a half meeting will bring together computational, crystallographic modelers and medicinal chemists to learn and share how these advances are affecting the optimization of compounds that target GPCRs.

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12:30 pm Registration

GPCR Structural Determinants 

1:30 Chairperson’s Opening Remarks

Scientific Advisor: Michael Hanson, Ph.D., Director, Structural Biology, Receptos


The Chemical and Structural Biology of S1P Receptor Therapeutics

Hugh RosenHugh Rosen, M.D., Ph.D., Professor, Chemical Physiology, Scripps Research Institute - Biography 

Approaches to S1P1 receptor therapeutics will be presented, including uHTS approaches, pharmacological clues for allostery, pocket mapping by mutagenesis, insights from a high-resolution S1P1 crystal structure, implications for signal bias and the biological consequences of receptor modulation.

2:40 Utilizing Structural Insights in GPCR Drug Discovery

Robert CookeRobert Cooke, Ph.D., Head, Biomolecular Structure Department, Heptares

The number of GPCRs for which structural information is available has increased dramatically in recent years, providing valuable insights into ligand recognition and mechanisms of activation, as well as additional starting points for homology modelling. Structure-based drug discovery is now a reality for this family, and the impact of new structures for family A and family B GPCRs will be reviewed.

3:10 Sponsored Presentation (Opportunity Available)

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:20 Delineating Determinants of Co-Operativity, Affinity and Bias for Allosteric Modulators of Metabotropic Glutamate Receptor 5

Karen J. Gregory, Ph.D., Post-Doctoral Fellow, Jeffrey Conn Laboratory, Pharmacology, Vanderbilt University; American Australian Association Merck Co. Foundation Fellow

Comparative modeling combined with the systematic mutagenesis has furthered our understanding of how metabotropic glutamate receptor 5 allosteric modulators exert their effects. We have identified key amino acids within the transmembrane domains that govern modulator affinity and/or cooperativity, as well as mutations that confer molecular switches in modulator pharmacology.

4:50 Mapping Allosteric Sites in GPCRs

Nagarajan Vaidehi, Ph.D., Professor, Immunology, Beckman Research Institute of the City of Hope

GPCRs are allosteric nanomachines that convey the ligand binding information on the extracellular surface to intracellular region. Experiments provide information on which residues are involved in either end of the allosteric communication but no information on the pathway of this communication. We have developed computational methods to map the allosteric pathway in GPCRs. These methods not only provide insights into the mechanism of communication but also provide new approaches to identifying allosteric druggable sites in GPCRs.

5:20 Moderated Breakout Discussions

In this interactive session, several topics will be offered for discussions and delegates are invited to choose a topic of interest and join the moderated discussion at hand. In this informal setting, participants are encouraged to share examples from their work, vet ideas with peers and be part of a group problem-solving endeavor. We emphasize that this is an informal exchange amongst scientists and is not meant to be, in any way, a product promoting session.

Topic: Identifying Druggable Sites from GPCR Structural Information

Moderator: Ruben Abagyan, Ph.D., Professor, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego

  • Successes and failures using computational structures as a guide
  • Using crystal structures as a guide
  • Dealing with allosteric modulators

Topic: Conformational Flexibility and its Impact on GPCR-Based Drug Design

Moderator: Jan Steyaert, Ph.D., Executive Director and Professor, Molecular and Cellular Interactions, Vrije Univ Brussels

  • How many GPCR structures will we need?
  • What about the different functional conformations of GPCRs?
  • Can we use structural data  to discover biased or allosteric ligands?

Topic: Docking into Homology Models of GPCRs: Is the Additional Complexity Worth the Effort?

Moderator: Carleton Sage, Ph.D., Fellow, Computational Systems, Arena Pharmaceuticals

• Ligand-based virtual screening
• Limits of template homology
• Docking into Orphan Receptors

6:20 End of Day

6:30 - 9:00 pm Dinner Short Courses (Separate registration required)

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