GPCR-Targeted Drug Design

with a Focus on Biased Signaling and Biophysical Techniques

April 24-25, 2017 | Sheraton San Diego Hotel & Marina




G protein-coupled receptors (GPCRs) are one of the most important classes of drug targets, with approximately one-third of currently marketed drugs having their effect through GPCRs. However, because the seven-membrane spanning structure of GPCRs makes them difficult to isolate and crystallize, this target class has historically benefited less from the computational chemistry approaches that have significantly facilitated drug discovery efforts for soluble protein targets. But over the past five years, due to advances in protein crystallization techniques and tricks to solubilize GPCRs, there has been an explosion in the number of x-ray crystal structures elucidated for GPCRs. This meeting will cover applications of this knowledge as well as other biophysical innovations that facilitate the discovery and optimization of GPCR-targeted ligands.


Final Agenda

Monday, April 24

7:00 am Registration and Morning Coffee


8:00 Chairperson’s Opening Remarks

Roger K. Sunahara, Ph.D., Professor of Pharmacology, University of California San Diego

8:10 Positive Allosteric Modulators of Opioid Receptors

Andrew_AltAndrew Alt, Ph.D., Associate Director, Biology, Arvinas

Positive allosteric modulators (PAMs) of opioid receptors block pain by amplifying the activity of endogenous opioid agonists which are naturally released in pain states. However, PAMs have no effect in tissues where agonists are not present. Therefore, opioid PAMs may exhibit significantly improved side effect and abuse liability profiles compared to current opioid medications. The current preclinical data supporting a rationale for developing opioid receptor PAMs as novel pain medications will be presented.

8:40 Conserved Allosteric Sodium in Opioid Receptors and other Class A GPCRs: Role in Function and Ligand Design

Seva_KatritchSeva Katritch, Ph.D., Assistant Professor, The Bridge Institute, University of Southern California

Opioid receptors, along with many other class A GPCRs, feature a highly conserved polar cavity in the center of 7TM bundle, harboring a sodium ion and water cluster with highly unusual properties. We will describe structural and pharmacological evidence for this Na+ cluster and its conservation in many GPCRs, as well as the recent efforts in elucidating its role in receptor function. We will also discuss emerging applications of the allosteric sodium site in GPCR stabilization and ligand discovery.


CollaborativeDrugDiscovery9:10 Modern Drug Research Informatics Applications to CNS, Infectious, Neglected, Rare, and Commercial Diseases

Barry Bunin, Ph.D., CEO, Collaborative Drug Discovery (CDD), Inc.

Collaborative innovation is uniquely able to realize the economics of well-integrated specialization required for chemical biology and drug discovery. Particularly in the neglected infectious disease areas lacking a profit motive, better collaborative tools are fundamentally important to catalyze faster progress. Layering unique collaborative capabilities upon requisite drug discovery database functionality unlocks and amplifies synergy between biologists and chemists.

9:40 Coffee Break

10:05Dual kappa-delta Opioid Agonists as Analgesics and Anti-Addiction Agents against Cocaine Abuse

Susruta_MajumdarSusruta Majumdar PhD, Assistant Attending, Department of Neurology, Memorial Sloan Kettering Cancer Center

Kappa receptor agonists are known to be agents with analgesic and anti-addictive properties whose therapeutic benefit is limited by dysphoria and sedation. We now report that dual activation of kappa and delta receptors leads to a separation of analgesia and cocaine blockade from aversion. Our findings suggest that activation of delta receptors alleviates kappa-mediated place aversion and could be an effective strategy to counteract kappa-mediated adverse effects.

10:35 Kratom Alkaloids: Novel Molecular Frameworks for Next-Generation Opioid Modulators

Andrew_KruegelAndrew Kruegel, Ph.D., Associate Research Scientist, Department of Chemistry, Columbia University

The Mitragyna speciosa plant (kratom) has been used in traditional medicine in Southeast Asia for hundreds of years. Alkaloids isolated from this plant and their synthetic derivatives act as opioid receptor modulators with pharmacological properties distinct from traditional opioids, namely they elicit potent analgesic effects in rodents while avoiding the major negative side effects of respiratory depression, tolerance/dependence, and reward. The design, synthesis, and pharmacological evaluation of new analgesics in this class will be discussed.

11:05 Opioid Receptor Trafficking and Signaling

Manoj_PuthenveeduManoj Puthenveedu, Ph.D., Associate Professor, Department of Biological Sciences, Carnegie Mellon University

Membrane trafficking, by determining the number of receptors available on the cell surface, can regulate the strength of cellular responses to signals. Emerging data suggest that trafficking can also tune cellular responses by regulating receptor location, and therefore the site of signal origin, in the cell. In this context, I will present our work on how trafficking changes sub-cellular localization of opioid receptors and thereby regulates opioid signaling.

Multispan11:35 Luncheon Presentation: Not All Cell Lines Are Created Equal - Impact of Surface Expression on GPCR Assays

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

GPCR screens require reproducible and reliable expression of the receptors in native or transfected cells. We developed a robust platform for generating GPCR stable cell lines and come to realize that the level of receptor expression affected our ability to measure activity such as partial or full agonist. We will share our screening platform and results using cells that differentially express receptors to show how critical the clone selection can impact outcome.

12:20 pm Session Break


1:15 Chairperson’s Remarks

Samantha J. Allen, Ph. D., Senior Scientist, Lead Discovery-Screening, Janssen Research & Development

Roger Sunahara1:20 FEATURED PRESENTATION: Receptor Allostery by Cations, Small Molecules and G proteins

Roger K. Sunahara, Ph.D., Professor of Pharmacology, University of California San Diego

The relationship between G protein binding and the hormone binding site, where G proteins potently enhance the affinity of hormone agonists, is an allosteric one. Here we describe a major role of additional co-factors, cations, as allosteric modulators in the stabilization of inactive and active states of GPCRs. These data highlight the complex nature of the cooperativity existing between hormones, cations and G proteins in stabilizing specific GPCR conformations and illustrate a significant impact on drug discovery and development.

1:50 Diverse Mechanisms for Nuclear Localization of GPCRs: Impact on Function

Sylvain_ChemtobSylvain Chemtob, M.D., Ph.D., Professor of Pediatrics and Ophthalmology, University of Montreal

Mechanisms that govern localization of GPCRs at the cell nucleus remain mostly unknown and vary. For instance, stimulation of coagulation factor II receptor-like 1 (F2rl1) leads to its translocation from plasma membrane to the cell nucleus using a microtubule-dependent shuttle that requires sorting nexin 11 (Snx11). Whereas stimulation of platelet-activating factor (PAFR) does not affect its cellular distribution. But its C-terminal motif, along with Rab11a and importin-5 are critical for nuclear localization of PAFR.

2:20 Biophysical Basis for Sustained G Protein Signaling by Internalized GPCRs

Alex_ThomsenAlex Thomsen, Ph.D., Postdoctoral Fellow, Lefkowitz Lab, Department of Medicine, Duke University

Some GPCRs activate G-proteins from within internalized cellular compartments resulting in sustained G-protein signaling rather than β-arrestin-mediated desensitization. Using a variety of biochemical, biophysical, and cell-based methods we recently demonstrated the existence, functionality, and architecture of internalized receptor “megaplexes” composed of a single GPCR, β-arrestin, and G-protein. Formation of such megaplexes provides a mechanistic explanation for how a GPCR, while being internalized through interaction with β-arrestin maintains its ability to activate G-protein from internalized compartments.

2:50Ozanimod: An S1P1,5R Modulator that Targets Lymphocyte Trafficking in Autoimmune and Inflammatory Disease

Kristin_MeadowsKristin Taylor Meadows, Ph.D., Scientist III, Biology, Receptos/Celgene

S1P1R is a GPCR expressed on lymphocytes mediating migration out of secondary lymphoid tissues. S1P1R modulators internalize the receptor, sequestering lymphocytes and preventing their migration to inflammation sites. The S1P1,5Rmodulator ozanimod is in clinical development to treat Multiple Sclerosis and Inflammatory Bowel Disease. This presentation will cover the pharmacological tools we used to identify a safe and effective S1P1,5R modulator and evidence that ozanimod utilizes different residues than FTY720-p in the orthosteric ligand binding pocket.

3:20 3DM Protein Family Analysis System Applied to the GPCR Protein Family

Henk-Jan Joosten, Ph.D., CEO, Bio-Prodict

Proteins fall in large protein-families and vast amounts of data are available for one protein family (e.g., sequences, literature, structural data, alignment data, SNP data, mutation data, binding data, etc.). 3DM, a protein-superfamily analysis platform, automatically collects all data and contains many state-of-the-art tools enabling complex analysis of superfamily data.

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing


PROTACs: Inducing Protein Degradation as a Therapeutic Strategy

Craig M. Crews, Ph.D., Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology; Professor, Chemistry & Pharmacology, Yale University

Enzyme inhibition has proven to be a successful paradigm for pharmaceutical development, however, it has several limitations. As an alternative, for the past 16 years, my lab has focused on developing Proteolysis Targeting Chimera (PROTAC), a new ‘controlled proteolysis’ technology that overcomes the limitations of the current inhibitor pharmacological paradigm. Based on an “event-driven” paradigm, PROTACs offer a novel, catalytic mechanism to irreversibly inhibit protein function, namely, the intracellular destruction of target proteins.


5:30 Welcome Reception in the Exhibit Hall with Poster Viewing


6:30 Close of Day

Tuesday, April 25

7:30 am Continental Breakfast Breakout Discussions

In this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers.

Topic: Biophysical Approaches to GPCR Drug Discovery

Moderator: Phillip Schwartz, Ph.D., Senior Scientist, Structural Biology and Biophysics, Takeda California

  • Physiological or mimetic, in what matrices should GPCRs be placed for biophysical characterization?
  • Promising new technologies to study GPCR-drug interactions
  • Fragment screening GPCRs: best methods and practices

Topic: New Ways to Screen GPCRs

Moderator: Samantha J. Allen, Ph. D., Senior Scientist, Lead Discovery-Screening, Janssen Research & Development

  • Physiologically relevant cells and assays
  • High-content screening
  • Newer assay kits
  • Understanding signaling bias

Topic: Structure-Based Design and Allosteric Modulators

Moderator: Sid Topiol, Ph.D., CSO, 3D-2drug, LLC; Professor and Director, Structural and Computational Drug Discovery, Stevens Institute of Technology

  • How can structural information help in the design of traditional allosteric modulators?
  • Can structural information expand the scope of allosteric modulation opportunities?
  • What role can allosteric modulation of transporters play for GPCR targets?
  • What challenges are associated with allosteric modulation


8:30 Chairperson’s Remarks

Sid Topiol, Ph.D.,CSO,3D-2drug, LLC;Professor andDirector,Structural and Computational Drug Discovery,Stevens Institute of Technology

8:35 GPCR Structural Biology for Drug Discovery: Through the Protein Science Lens

Sujata Sharma, Ph.D., Director, Screening and Protein Science, Merck and Company

9:05 X-ray Structures of GPCRs and Related Transporters: New Opportunities Emerging for Old Targets

Sid TopiolSid Topiol, Ph.D.,CSO,3D-2drug, LLC;Professor andDirector,Structural and Computational Drug Discovery,Stevens Institute of Technolog


TCG Life Sceinces9:35 Coffee Break in the Exhibit Hall with Poster Viewing



10:30 Biophysical Characterization of GPCRs: SPR and Other Techniques

Phillip_SchwartzPhillip Schwartz, Ph.D., Senior Scientist, Structural Biology and Biophysics, Takeda California

Drug-discovery efforts are undergoing a renaissance in GPCR-related research as orphan receptors become de-masked and our understanding of how to study these difficult targets improves. Identifying preparations amenable to biophysical characterization is a critical step in pursuing GPCR drug development. We are pioneering the application of numerous biophysical techniques including SPR, SHG, DSF, NMR, HDX and BSI to study GPCRs. Data from a variety of these techniques will be compared and contrasted using a number native ligands and tool compounds.

11:00 Conformational Dynamics of G Protein-Coupled Receptors as Studied by NMR Spectroscopy in Solution

Matthew_EddyMatthew Eddy, Ph.D., Postdoctoral Fellow, Laboratory of Raymond Stevens, The Bridge Institute, University of Southern California

Application of nuclear magnetic resonance (NMR) spectroscopy to studies of G protein-coupled receptors (GPCRs) has been challenging due to difficulties producing sufficient quantities of isotope labeled functional receptors. Here we present a novel approach to heterologous production of wild type, labeled human GPCRs at sufficient quantities and quality for high resolution NMR spectroscopy. Data obtained with our method provide novel insights into intrinsic ligand activity that may aid in developing new design criteria for drugs that target GPCRs.

11:30 Ligand-observed NMR for Ligand Selectivity and Fragment Screening of Specific GPCR Subtypes

Daniel_ScottDaniel Scott, Ph.D., Laboratory Head, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne

We evolved ultra-stable α1A-AR and α1B-AR variants using Cellular High-throughput Encapsulation, Solubilization and Screening (CHESS) to enable the analysis of ligand binding and fragment screening using ligand observed NMR techniques. α1A- and α1B-adrenoceptors (α1A-AR and α1B-AR) are closely related G protein-coupled receptor (GPCRs) that modulate the cardiovascular and nervous systems in response to binding epinephrine and norepinephrine.

12:00 pm Close of Conference