Day 1  |  Day 2 |  Short Courses |  Download Brochure 

SUNDAY, NOVEMBER 1

Recommended Short Courses* 12:00 pm - 3:00 pm Targeting GPCRs and Ion Channels with Antibodies (SC2)* 3:30 pm - 6:30 pm Combating Diabetes with Strategies for Enhanced Pancreatic Beta Cell Survival and Regeneration (SC4)* 3:30 pm - 6:30 pm Structure Based Design of Ion Channels (SC5)* *Separate Registration Required

 

MONDAY, NOVEMBER 2

7:00 am Registration and Morning Coffee

APPLYING STRUCTURE-BASED KNOWLEDGE TO GPCR DRUG DISCOVERY

8:30 Chairperson’s Opening Remarks

 

9:10 The Impact of Recent X-Ray Structure Determinations on Structure-based Drug Design for GPCRs and other CNS Targets

Sidney W. Topiol, Ph.D., Associate Director, Computational Chemistry, Lundbeck Research USA, Inc.

While Structure-based Design has become a powerful tool in drug discovery, its role in compound design and screening for CNS targets, which are often membrane-bound proteins, has been more limited. This has been due to the difficulty in obtaining X-ray structures for these targets. Significant recent successes in X-ray structure determinations are rapidly advancing this field. These findings, as well as early evidence of their impact on targets such as (Class A and C) GPCRs and Transporters, are reviewed.

9:40 The Structure of G Protein Coupled Receptors: Implications for Signaling and Pharmacology

Gebhard F. X. Schertler, Ph.D., Senior Scientist, Group Leader, MRC Laboratory of Molecular Biology, Cambridge, UK

We have studied the structure of rhodopsins and adrenergic receptors. New insights into the activation of rhodopsin allow us to interpret some of the stabilizing mutations found in the beta 1 adrenergic receptor. Our most recent structures of the beta 1 adrenergic receptor with a number of different ligands has important implications for basal activation and constitutive activation of receptors.

10:10 Grand Opening Coffee Break in the Exhibit Hall

10:40 Mapping Ligand Specific States for Drug Design in GPCRs

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

GPCRs undergo conformational changes even in the absence and presence of ligands of varied efficacies. These conformational changes are important and should be considered for drug design for obtaining subtype specificity. Here we will demonstrate how our computational methods account for this conformational flexibility and show selectivity and enrichment of ligands in a virtual screen. These computational methods can also be used to optimize homology based models used in modeling GPCRs in pharmaceutical companies.     

11:10 Monitoring the Multiple Signaling Pathways of GPCRs: Insights into the Molecular Determinants of Ligand-Biased Signaling

Michel Bouvier, Ph.D., Professor, Biochemistry, Institute for Research in Immunology and Cancer, University of Montreal

According to receptor-occupancy theory, efficacy of a ligand is considered an intrinsic property of the ligand/receptor pair, and is often assumed to be the same for all the responses evoked. However, recent observations indicate that distinct signalling pathways engaged by a specific receptor can be differentially regulated by a given ligand that can sometimes have inverse efficacies on different signalling output (ligand-biased signalling). We describe a novel assay system allowing us to monitor multiple signalling pathways and to assess the structural determinants of ligand-biased signalling.

11:40 Using Stabilised GPCRs to Enable Structure Based Drug Discovery

Fiona Marshall, Ph.D., Founder and Chief Scientific Officer, Heptares Therapeutics Limited

Modern methods in drug discovery which are routinely applied to soluble targets include a range of methods such as X-ray crystallography, virtual screening, fragment screening and biophysical techniques such as NMR and Surface Plasmon Resonance. GPCR drug discovery has been hampered by the requirement to be assayed within the plasma membrane since removal from the membrane results in rapid denaturation. Techniques to stabilize receptors through limited mutagenesis allow GPCRs to be extracted from the plasma membrane in soluble, properly folded states. Data will be presented on the use of such stabilized receptors or StaRsTM  in structure based drug discovery.

12:10 pm Cell-Based Assays for G-Protein Independent Signaling Using Arrestin Binding and Endocytosis  

Tom Wehrman, Ph.D., Director of Cell Biology, Research and Development, DiscoveRx Corporation

GPCR signaling is associated with G-protein activation that couples to either the cyclic AMP or calcium pathways. GPCR activation also initiates a host of cellular responses that regulate function and activate alternative pathways that are independent of G-protein activation. Two major G-protein independent events are arrestin recruitment and internalization of the activated GPCR. Previously, we developed a system to monitor protein-protein interactions using enzyme fragment complementation (EFC). Attendees will learn how to employ this system to monitor the interaction of GPCRs with arrestin as well as follow activated GPCR trafficking within the cell using a single step, HTS-friendly assay format.

12:40 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

NEW METHODS FOR PROBING OR SCREENING GPCRS

2:20 Chairperson’s Remarks

2:25 Targeting GPCR Activity: Conventional and Novel Label-free cAMP Assays

Sandra Siehler, Ph.D., Research Investigator II, Novartis Institute for BioMedical Research

This presentation will cover drug discovery strategies for GPCRs and GPCR-related cAMP signaling. Fluorescent, luminescent, and innovative label-free cAMP assay technologies using cellular and biochemical approaches will be discussed.

2:55 Hit Identification Practices for GPCR Targets at Bristol-Myers Squibb Company

Neil Burford, Ph.D., Senior Research Investigator, Lead Discovery, Bristol-Myers Squibb Company

Recent advances in HTS process, assay technologies, and receptor biology has led to some significant changes in hit identification strategies for GPCR targets over the past few years. In this presentation, current GPCR hit identification practices and challenges, at Bristol-Myers Squibb, will be highlighted.

3:25 Allosteric Regulation of Agonist and Inverse Agonist Binding to Monomeric GPCRs by G Proteins

Roger Sunahara, Ph.D., Assistant Professor, Pharmacology, University of Michigan Medical School

Although GPCRs are capable of forming oligomers, the functional contributions of oligomerization, with a few exceptions, are less understood. We use nanometer-scale particles High Density Lipoprotein (HDL) particles to reconstitute purified preparations of three Family A GPCRs: b2-adrenergic receptor, bovine rhodopsin and the m-opioid receptor. We provide pharmacological and biophysical evidence that agonist and inverse agonist binding to monomeric forms of all three receptors are efficiently and allosterically modulated by G proteins. These data highlight the limited role that GPCR oligmerization may play in G protein activation of these Family A receptors.

3:55 Networking Refreshment Break in the Exhibit Hall

4:30 Pepducins – Novel Mediators of GPCR Signaling

Stephen Hunt, III, Ph.D., Senior Vice President, Discovery Research, Ascent Therapeutics

Pepducins are a breakthrough approach to targeting G-protein coupled receptors (GPCRs) on the inside surface of the cell membrane, dramatically expanding the GPCR frontier. Pepducins are comprised of a short peptide derived from a GPCR intracellular loop linked to a hydrophobic moiety. This structure allows Pepducin lipopeptides to anchor in the cell membrane lipid bilayer and modulate GPCR activity via a unique intracellular allosteric mechanism. Pepducin technology represents an exciting new area of research directed towards a well-validated class of drug targets and will be the focus of this presentation.

5:00 Testing the Hypothesis of Allosteric Compound Selectivity through Large Scale
Selectivity-Profiling

Blaine Armbruster, Ph.D., Manager, GPCR Drug Discovery, Millipore Corporation

Among the many expected advantages of allosteric compounds is a higher level of selectivity compared to orthosteric compounds. This assumption is based on the premise that, unlike orthosteric compounds, allosteric compounds interact with fairly non-conserved binding sites. We have developed a cell-based method to reliably screen the functional selectivity of allosteric compounds across a broad panel of 155 GPCRs, which will be presented.

5:15 Membrane-tethered Ligands Provide a Novel Strategy for Modulating GPCR Function

Alan S. Kopin, M.D., Professor of Medicine, Director, Molecular Pharmacology Research Center, Tufts University Medical

We have developed a novel technology in which a peptide ligand tethered to the cell membrane can selectively modulate the function of its cognate GPCR. The approach is demonstrated using a series of class B1 (secretin family) GPCRs. The recombinant constructs encode a transmembrane domain anchor linked to an extracellular peptide ligand with a free N terminus. We demonstrate that tethered ligands are highly efficacious, receptor selective, can be engineered to have either agonist or antagonist activity, and are functional both in vitro and in vivo. Membrane tethered ligands thus offer a powerful new approach to enhance the understanding of GPCR mediated biology.

5:45 Happy Hour in the Exhibit Hall

7:00 Close of Day

Day 1  |  Day 2 |  Short Courses |  Download Brochure 

---