2015 Archived Content

Despite their fruitful history in the drug development industry, discovering or designing new therapeutic agents that modulate a GPCR in a specific way is still a challenge, and in fact is undergoing a renewal because of explosion of new knowledge about their structure and ways to more precisely control their signaling via which G protein or other receptor-associated protein they couple to (biased signaling). Part 1 of CHI’s back-to-back GPCR meetings will focus on structural aspects of GPCRs and new assays, technologies and approaches for discovering and designing GPCR-targeted compounds.

Final Agenda

Day 1 | Day 2 | Download Brochure

Tuesday, September 22

7:00 am Registration and Morning Coffee


8:00 Chairperson’s Opening Remarks

Vsevolod (Seva) Katritch, Ph.D., Assistant Professor, The Bridge Institute and Department of Biological Sciences, University of Southern California

8:10 Structural Biology of the Lipid Receptors

Mike Hanson, Ph.D., Director, GPCR Consortium

The lipid binding receptors have been widely studied using biochemical methods. The structure of the S1P1 receptor has been used to understand the binding mode of compounds for the treatment of relapsing multiple sclerosis. Recently, structural analysis of the LPA1 receptor has revealed alternate binding modes for lipid ligands that may be more permissive for binding a wide array of endogenous lipid ligands.

8:40 Computational Methods to Identify Allosteric Binding Sites for Design of Biased Ligands for GPCRs

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

We have developed a computational method to identify residues that modulate the the allosteric communication from the extra-cellular to the intra-cellular domain of the receptor. This is useful for predicting residues that govern the biased signaling in GPCRs. I will demonstrate how this method can be used to predict allosteric binding sites that can be used to design biased ligands.

9:10 Chemokines and their Receptors: Insights from Modeling and Crystallography

Irina Kufareva, Ph.D., Project Scientist, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego

Chemokines control cell migration in the context of immunity, inflammation, and development, by virtue of binding and activating 7TM chemokine receptors on the cell surface. The structural basis of this interaction remained elusive for many years, until we first accurately modeled and then solved experimentally a structure of the CXCR4:chemokine complex. Structural insights into recognition specificity, affinity and pharmacology of natural and engineered chemokine ligands of CXCR4 and other chemokine receptors will be presented. 

9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:25 GPCR Crystallography by XFELs

Wei Liu, Ph.D., Assistant Professor, Department of Chemistry and Biochemistry, Arizona State University

The recent appearance of X-ray free-electron lasers (XFELs) has enabled structure determination from substantially smaller crystals than previously possible with minimal effects of radiation damage, offering new exciting opportunities in structural biology. The unique properties of LCP material have been exploited to develop special protocols and devices that have established a new method of serial femtosecond crystallography of GPCRs in LCP.

10:55 Targeting Purinergic P2Y Receptors for Structure-based Ligand Discovery 

Vsevolod (Seva) Katritch, Ph.D., Assistant Professor, The Bridge Institute and Department of Biological Sciences, University of Southern California

Purinergic signaling underlies key cardiovascular, immune, digestive, nervous and endocrine function and disease, and is involved in cancer.  Crystal structures of P2Y12 and P2Y1 receptors in complexes with antagonists, agonists and most recently with an allosteric modulator reveal an amazing shapeshifting nature of these purinergic receptors. This structural information is being actively employed in discovery of tool compounds and new generation of drug candidates.

11:25 A Negative Allosteric Nanobody to the Beta-2-Adrenergic Receptor Reveals New Insights into Molecular Efficacy

Dean Staus, Ph.D., Post-doctoral Fellow, Laboratory of Robert Lefkowitz, Duke University Medical School

We have identified a nanobody (Nb60) against the beta-2-adrenergic receptor (β2AR) that stabilizes an inactive state conformation as assessed by pharmacological, biophysical, and crystallographical analysis. By measuring the effect of Nb60 and Nb80 (previously characterized active state stabilizing nanobody) on the affinity of 17 different β2AR ligands, we have found that differences in ligand efficacy can be derived by both induction and repression of specific active and inactive receptor states.

11:55 Interrogating Ligand:Target Integrations using Back-Scattering Interferometry Yields Mechanistic Insights and Aids in Compound Prioritization

Layton Harris Smith, Ph.D., Director, Drug Discovery – Florida, Sanford Burnham Prebys Medical Discovery Institute

Integral membrane proteins such as GPCRs are critical targets for drug discovery but present a host of challenges to the characterization of their binding affinities for small molecules. Determination of allosteric binding in GPCR targets is especially valuable and extremely challenging information to obtain by established binding assay platforms, but can be addressed through a label-free solution-based direct-binding technology, back-scattering interferometry (BSI).

12:25 pm Session Break

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:15 Refreshment Break in the Exhibit Hall with Poster Viewing


1:50 Chairperson’s Remarks

Brian J. Arey, Ph.D., Senior Principle Scientist, Cardiovascular Drug Discovery, Bristol-Myers Squibb Co.

1:55 KEYNOTE: New Structural and Biological Insights to Functional Selectivity

Bryan_RothBryan Roth, Ph.D., Professor, Department of Pharmacology, University of North Carolina Medical School

GPCRs remain the single largest family of molecular targets for therapeutic drug discovery. In this talk I will describe recent ongoing efforts to discover and validate novel small molecules for modulating GPCR activity in therapeutically relevant ways.

2:30 GPCR Kinetic and Conformational Dynamics

Thomas P. Sakmar, M.D., Professor, Chemical Biology and Signal Transduction, The Rockefeller University

Genetic-encoding of unnatural amino acids can facilitate bioorthogonal labeling reactions to introduce site-specific fluorophores into expressed GPCRs. Labeled receptors and ligands can be used in single-molecule-detection (SMD) imaging assays to measure conformational dynamics and kinetics of ligand exchange reactions. We have developed a novel technology platform to perform automated, semi-high throughput SMD microscopy assays to study ligand-receptor interactions.

3:00 All Functional Assays in One Cell Line for Studying GPCR Signaling Bias

Lisa Minor, Ph.D., Business Development Consultant, Multispan, Inc.

G protein-coupled receptors (GPCRs) is the biggest therapeutic target class in drug discovery. Early models of the functional activity of GPCRs considered a classical two-state model: 'on' or 'off'. Based on this model, the properties of ligands were classified as agonists, antagonists, and inverse agonists. However, it is now clear that a given ligand is able to induce multiple signaling pathways, such as activation of G proteins and/or β-arrestin. Moreover, if more than one G-alpha protein subtype binds to its cognate receptor, each class of ligand could also affect the downstream signaling differently. These ligand properties are described as the functional selectivity or biased agonism and would, in principle, allow the selective activation of specific cell responses and physiological pathways. It is now well-accepted that many orthosteric ligands have the ability for bias signaling between different G proteins and/or between the G proteins and β-arrestins that are involved in receptor desensitization, internalization, and other second messenger signaling. Similar biases also apply to antagonist and modulators. In this report, we present our comprehensive recombinant assay system that allows us to examine different signaling pathways in the same cell line, obviating the misleading complications associated with using different cells for different assays. Specifically, data on optimized functional assays encompassing radioligand binding, GTPgS binding, cAMP, calcium, pERK, pNFkB, pGSK2, and internalization for LPA1, β1-adrenergic, and MOR receptors will be shared.

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Winner Announced

4:10 Biased Signaling as a Common Theme in Receptor Signaling

Brian J. Arey, Ph.D., Senior Principle Scientist, Cardiovascular Drug Discovery, Bristol-Myers Squibb Co.

Stabilization of receptor conformation has been suggested to be at the heart of functional selectivity of GPCRs. Non- GPCR receptors also display protein movements upon ligand-binding. Therefore, it is likely that biased signaling may occur as a common biological mechanism for inducing ligand- specific effects across receptor classes. Here, we will explore this concept using data from the literature.

4:40 Human Cannabinoid Receptor CB2: Expression, Functional and Structural Studies

Alexei Yeliseev, Ph.D., Staff Scientist, LMBB, NIH/NIAAA

Human cannabinoid receptor CB2 is a GPCR involved in regulation of immune response and is of therapeutic interest. I describe studies of the structural dynamics of CB2 bound to various types of cannabinoid ligands, in detergent micelles and in lipid bilayers in the form of proteoliposomes and lipoprotein particles (nanodiscs). I will also present 19F-NMR and EPR experiments on the receptor.

5:10 Interactive Breakout Discussion Groups

This interactive session provides conference delegates and speakers an opportunity to choose a specific roundtable discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion.

New GPCR Screening Approaches

Samantha J. Allen, Ph.D., Associate Principal Scientist, Protein Sciences, Merck

  • High content screening’s place in lead discovery
  • New technologies: biosensor applications, label-free assays
  • Screening for biased signaling

Receptor Structure

Irina Kufareva, Ph.D., Project Scientist, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego

  • What role can molecular dynamics simulations play in GPCR ligand design?
  • How can we predict, validate and leverage multiple binding sites on GPCRs?
  • When will we have a GPCR structure with beta arrestin bound and what might we learn?

Biophysical approaches for Studying GPCRS

Niek Dekker, Ph.D., Principal Scientist, Discovery Sciences, AstraZeneca

  • Fragment-screening
  • Crystallography
  • SPR
  • GPCR purification

6:10 Welcome Reception in the Exhibit Hall with Poster Viewing

7:15 Close of Day

Day 1 | Day 2 | Download Brochure

Wednesday, September 23

7:30 am Registration and Morning Coffee


8:00 Chairperson’s Remarks

Mike Hanson, Ph.D., Director, GPCR Consortium

8:10 Fragment-Based Lead Generation on a Proteinase-Activated GPCR

Niek Dekker, Ph.D., Principal Scientist, Discovery Sciences, AstraZeneca

We report discovery of antagonists of protease-activated receptor-2 using fragment-based approaches on a stabilized GPCR receptor. The novel PAR2 crystal structure explains why Vorapaxar is not active on this receptor. The biophysical and structural platform provides an excellent basis for the discovery of novel drugs on this challenging receptor.

8:40 The Power of Multi-Faceted Live-Cell Molecular Pharmacology Profiling

Kevin Pfleger, Ph.D., Associate Professor, Molecular Endocrinology & Pharmacology, Harry Perkins Institute of Medical Research, University of Western Australia

Getting to grips with mechanism of action requires us to understand as many facets of the pharmacological profile as possible. For GPCRs this includes binding, coupling to various G proteins, recruitment of arrestins, signalling through multiple different pathways, internalization, trafficking and recycling. Layered on top of this are the concepts of biased signaling and receptor heteromerization.

9:10 New, Rapid GPCR-Screening Methods for Drug Discovery

Samantha J. Allen, Ph.D., Associate Principal Scientist, Protein Sciences, Merck

The emerging complexity of GPCR biology has led to an increased desire to discover new types of modulators (e.g. PAMs, NAMs etc). I’ll discuss novel technologies we use to rapidly identify and characterize screening hits. I will also describe our use of robotics for high-throughput expression testing, binding and analysis of GPCRs to enable biophysical studies.

9:40 Coffee Break in the Exhibit Hall with Poster Viewing

10:25 Real-Time, SPR Monitoring of Small Molecule Binding Events on a Nanodisc-Reconstituted GPCR

Nicolas Bocquet, Ph.D., Scientist, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche

In this work we defined a new strategy to enable Surface Plasmon Resonance (SPR) measurements on an adenosine (A2A) G protein coupled receptor (GPCR) inserted in nanodiscs in a -label and detergent- free manner. We were able to detect and monitor small molecules binding kinetics by SPR and to provide a comparison between different binding assays format on A2A receptors in native membranes, reconstituted in nanodiscs or solubilized in detergent micelles.

10:55 Targeting Multiple GPCRs Simultaneously for CNS Disorders

Hugo Geerts, Ph.D., CSO, Computational Neuropharmacology, In Silico Biosciences

We have developed a Quantitative Systems Pharmacology platform that captures biophysically accurate representations of human firing networks and is calibrated with human imaging and clinical data. Reverse-engineering such platform offers the opportunity to identify a lean pharmacological profile of GPCRs that would support a rationally designed multi-target medicinal chemistry program. We will show an example in the field of schizophrenia.

11:25 Enjoy Lunch on Your Own

12:55 pm Plenary Keynote Program

2:40 Refreshment Break in the Exhibit Hall with Poster Viewing

3:25 Close of Conference

Day 1 | Day 2 | Download Brochure

Suggested Event Package:

September 21 Short Course: GPCR Structure-Based Drug Discovery

September 21 Short Course: Targeting of GPCRs with Monoclonal Antibodies

September 22-23 Conference: GPCR-Based Drug Discovery, Part 1

September 23-24 Conference: GPCR-Based Drug Discovery, Part 2

September 23 Short Course: Introduction to Allosteric Modulators and Biased Ligands of GPCRs