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MONDAY, OCTOBER 1

7:00 am Conference Registration and Morning Coffee

New Structural Insights

8:30 Chairperson's Opening Remarks

Neil Burford, Senior Research Investigator II, Lead Discovery & Profiling, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company
 

9:10 Nanobodies for the Structural Analysis of GPCR Transmembrane Signaling

Jan Steyaert, Ph.D., Professor, Structural Biology Department, Vrije University of Brussels

Nanobodies are small (15 kDa) and stable single domain fragments harboring the full antigen-binding capacity of the original heavy chain only antibodies that naturally occur in Camelids. Because of their unique three-dimensional structure, nanobodies have access to cavities or clefts on the surface of proteins. We identified nanobodies that stabilize the b2AR•Gs complex. One of these nanobodies was used to obtain the high resolution crystal structure of this complex, providing the first view of transmembrane signaling.

9:40 How Drugs Bind and Control Their Targets: Characterizing GPCR Signaling through Long-Timescale Simulation

Ron Dror, Ph.D., Senior Research Scientist, D. E. Shaw Research

We report on GPCR-related results from our special-purpose machine that accelerates molecular dynamics simulations of biomolecular systems. Unbiased simulations in which drugs spontaneously associate with GPCRs to achieve bound conformations that match crystal structures almost perfectly are now possible (Nature 482:552-6, 2012). Simulations have also captured transitions of the β2-adrenergic receptor between its active and inactive states, allowing us to characterize the mechanism of receptor activation.

10:10 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

Screening Strategies

10:40 Session and Panel Introductory Remarks: Probes and Assays for GPCRs

Neil Burford, Senior Research Investigator II, Lead Discovery & Profiling, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company
 

10:55 Biased Signaling and the use of High Content Assays

Andrea Weston, Ph.D., Senior Research Investigator II, Cellular Systems Group, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company

As the inherent complexity of GPCR biology continues to unfold, and the opportunities afforded by exploiting phenomena such as biased agonism and allosteric modulation become more apparent, we have found increasing value to leveraging high-content imaging assays to characterize GPCR ligands. The use of high-content screening to enhance GPCR drug discovery efforts at BMS will be discussed, with focus on the detection and characterization of ligand bias and the study of GPCR internalization and trafficking kinetics.
 

11:25 Optical Micro-Spectroscopy Instrumentation and its Application to the Determination of the Quaternary Structure and Distribution in Living Cells of GPCR Homo-Oligomers

Valerica Raicu, Ph.D., Associate Professor, Physics, University of Milwaukee Wisconsin 

This presentation will introduce a novel micro-spectroscopic technique for FRET-based determination of the quaternary structure and localization in living cells of membrane protein complexes and will review results obtained from our recent studies of several G protein-coupled receptors (GPCRs) in living cells.

11:40 Screening Case Studies Using Label Free Approaches

Hong Xin, Ph.D., Scientist/Technologist, Lead Generation, Johnson & Johnson PRD

12:40pm LUNCHEON PRESENTATION
Investigating Receptor Biology Using PathHunter® Technology: Application to GPCR Trafficking and Internalization

Liz Quinn, Ph.D., Marketing Director, LeadHunter Discovery Services, DiscoveRxThe PathHunter system has been employed to monitor protein interactions and translocation in a cell-based, HTS-friendly format. This technology enables the generation of cellular assays for intractable targets and simplifies detection of cellular signaling events using a simple, one-step chemiluminescent protocol. We previously commercialized >220 GPCR targets that monitor receptor activity through Arrestin recruitment. Here, we discuss the application of the technology to receptor trafficking in response to pharmacochaperone activity and receptor internalization in response to agonist activation.

GPCR-Targeted Drug Candidates

2:20 Chairperson's Remarks

2:25 Discovery of an Orally Available Prostacyclin (PGI2) Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension

Graeme Semple, Ph.D., Vice President, Discovery Chemistry, Arena Pharmaceuticals, Inc.

The design and optimization of new prostacyclin receptor agonists with oral activity in rat models of pulmonary arterial hypertension will be described. As well as in vitro and in vivo potency, special attention was paid to pharmacokinetic parameters eventually resulting in the discovery of the clinical candidate, APD811.

2:55 Case Study in Quantifying Potency and Mode of Action of a Small Molecule Antagonist of a Class B Receptor, CRF1

Simeon Ramsey, Ph.D., Senior Principal Scientist, Inflammation, Pfizer

This presentation will highlight the utility of a non-equilibrium receptor-ligand binding assay to quantify the binding kinetics of small molecule antagonists to the CRF1 receptor and how data from this platform was used to explain apparent non-competitive, insurmountable antagonism observed in cell based functional assays. It also demonstrates how these kinetic data can be used to design, interpret and predict in vivo receptor occupancy.
 

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing

4:05 Orexin Receptors and the Physiology/Pharmacology of Sleep

Timothy Lovenberg, Ph.D., Senior Research Fellow, Neuroscience, J&J La Jolla

This talk will cover the distinct roles of Orexin-1 and Orexin-2 receptors in the sleep-inducing effects of Orexin receptor antagonists.

4:35 Targeting Novel Regulatory Mechanisms of PDE4 as Potential New Treatments for Mood Disorders

James A. Bibb, Ph.D., Associate Professor, Departments of Psychiatry, and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center

A new regulatory mechanism by which PDE4 is activated in brain will be presented as a novel target for therapy development. We will demonstrate the antidepressant effects of disrupting this mechanism using small interfering peptides in animal paradigms modeling depression. This may be the first demonstration that it is sufficient to target cAMP/PKA activity in the nucleus accumbens to achieve antidepressant-like effects. Our results underscore the potential of selectively targeting intracellular signaling mechanisms for drug development.

6:15 – 7:30 Welcoming Reception in the Exhibit Hall with Poster Viewing

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