2016 Archived Content

GPCR-Based Drug Discovery - Part 1 Header

G protein-coupled receptors (GPCRs) have steadily remained an important target class for drug discovery because of the myriad of biological processes they initiate as transducers of extracellular signals to inside the cell. The first meeting in our two-part set of conferences, Part 1: Screening and Structure-based Approaches, will include presentations and discussions related to discovering and designing compounds that act on GPCRs. Recent advances in biophysical approaches to studying GPCRs have enabled progress in both, structure-based design of ligands for GPCRs, and new screening methods, which though not as high throughput as traditional cell-based assays, allow receptors to be studied in more relevant cellular contexts.

Final Agenda


• September 19 Short Course: GPCR Structure-Based Drug Discovery

• September 20-21 Conference: GPCR-Based Drug Discovery - Part 1

• September 21-22 Conference: GPCR-Based Drug Discovery - Part 2

• September 21 Short Course: Introduction to Allosteric Modulators

Day 1 | Day 2 | Download Brochure

Tuesday, September 20

7:00 am Registration Open and Morning Coffee


8:05 Chairperson’s Opening Remarks

Andrew Alt, Ph.D., Senior Research Investigator, Lead Discovery, Bristol-Myers Squibb


Gebhard F.X. Schertler, Ph.D., Professor, Head of Biology and Chemistry, Paul Scherrer Institute

By combined analysis of chemical shift changes from GPCR point mutations in a thermostabilized mutant of the turkey β1-adrenergic receptor (β1AR) with ligand responses to the mutated receptors, we were able to identify crucial connections in the allosteric activation pathway of the receptor. This approach represents a general experimental method to delineate signal transmission networks at high resolution in GPCRs.

8:50 GPCR Dynamics as Revealed by NMR

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

To understand the function of G Protein-Coupled Receptors (GPCRs), deeper insight is needed into the role of conformational dynamics in molecular recognition and activation. Nuclear magnetic resonance (NMR) is uniquely suited to deliver information about dynamics at atomic resolution and over a large range of time scales. However, application of NMR to study GPCRs has so far been very challenging. I will present advances in the field that address some of these challenges and reveal initial insights into mechanisms of GPCR activation.

9:20 Combining Biophysical Techniques to Identify and Optimize New Chemical Entities in Targeted GPCR Drug Discovery

Daniel Mattle, Ph.D., Roche Postdoctoral Research Fellow, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel

We investigate new small molecular therapeutics to treat autosomal dominant retinitis pigmentosa (RP) caused by the GPCR rhodopsin. Our effort focuses on a combination of virtual screening, in vitro biophysical binding assays and structure determination of rhodopsin-ligand complex. Our tool platform enables fast and reliable identification and optimization of new hits towards leads for rhodopsin caused RP and any other GPCR involved in diseases.

9:50 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:35 Nanobody-Enabled Fragment Screening on GPCRs

Jan Steyaert, Ph.D., Vice-Director, Structural Biology Research Center, Vlaams Instituut voor Biotechnologie and Senior Advisor, ConFoTherapeutics

Progress in GPCR drug discovery has been disappointing. New compounds need to target the correct receptor, but the drugs must also exhibit the appropriate efficacy profile: (inverse) agonist, antagonist or biased ligand. We present a nanobody-enabled fragment screening approach to identify fragments that exclusively bind to particular functional conformations of the receptor allowing us to triage hits according to efficacy profile and potency.

11:05 A2AR Ligand Binding Kinetics Using Fluorescence Anisotropy: Determining Binding Rates in the Ligand Depletion Regime

Anne Robinson, Ph.D., Professor and Chair, Chemical & Biomolecular Engineering, Tulane University

We have developed a system to measure kinetics (on and off rates for different ligands/drugs) based on fluorescence anisotropy that allows label-free comparison of potential novel drugs. Here, ligand binding kinetics of the full-length human A2AR reconstituted in detergent micelles were measured using a fluorescently labeled ligand and fluorescence anisotropy. This approach, and the implications for drug discovery, will be described.

11:35 The Influence of Local Ligand Concentration on Observed Receptor Binding Kinetics: Measuring Drug Concentration Where it Matters

Steven Charlton, Ph.D., Professor, Molecular Pharmacology, University of Nottingham

Most current pharmacological approaches assume the interacting molecules are homogeneously distributed in solvent, but this is not necessarily the case for GPCRs where the membrane provides an additional compartment into which drugs may partition. This talk will discuss biophysical approaches to measure local drug concentrations at a sub-cellular level and explore the effects on observed receptor binding kinetics, building “micro PK/PD relationships” for receptor ligands.

12:05 pm Harnessing TruBind™ Technology to Enable Label-Free, Solution-Based Affinity Measurements for GPCR Target Engagement and MOA Studies

Richard Isaacs, Ph.D., Applied Research Sciences Manager, Molecular Sensing, Inc.

GPCRs are critical targets for drug discovery but present a host of challenges to the characterization of their binding affinity for small molecules. Verification of target engagement by putative GCPR ligands and further determination of mechanism of action for agonist/antagonist/allosteric compounds is especially valuable and extremely challenging information to obtain by established binding assay platforms, but can be addressed through the label-free solution-based TruBind platform based on back-scattering interferometry.

BioProdict12:35 3DM Protein Family Analysis System Applied to the GPCR Protein Family

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

Proteins often fall in large protein families (e.g 65.000 GPCR sequences are available). 3DM systems contain huge amounts of data (sequence-, structure-, mutation-, literature-, patent-, and binding data) for complete protein-families. 3DMs analysis suite (structure visualization-, literature/patent analysis-, correlated mutation-, mutation prediction-) connect all data/tools enabling state-off-the-art analysis.

12:50 Session Break

Multispan12:55 Luncheon Presentation: Not All Cell Lines Are Created Equal - Developing and Validating GPCR Assays for Screening

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

GPCRs are one of the most pharmaceutically proven targets in drug discovery. There are several ways to screen for activity against GPCRs, calcium mobilization, receptor binding, cAMP increases etc. One unifying feature of these screens is the requirement for reproducible and reliable expression of the receptor in native or transfected cells. At Multispan, we have developed a robust platform for the development and production of stably transfected GPCR expressing cells. In our efforts, we have come to realize that the level of expression of the receptors affects the ability to measure activity such as partial or full agonist, and so it is critical to evaluate multiple cell clones to ensure that the screen identifies compounds of interest. In this talk, we will share our screening platform and results using cells that deferentially express receptors to show how critical the selection of clones can impact outcome.

1:25 Refreshment Break in the Exhibit Hall with Poster Viewing


2:05 Chairperson’s Remarks

Samantha J. Allen, Ph.D., Senior Scientist, Emerging Science& Innovation, Janssen Research Labs

2:15 The Changing Landscape in GPCR-Targeted Drugs

Andrew Tebben, Ph.D., Senior Principal Scientist, Molecular Structure and Design, Bristol Myers Squibb Co.

2:45 GPCR Structural Biology for Drug Discovery: Through the Protein Science Lens

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

3:15 Modern Drug Research Informatics Applications to CNS, Infectious, Neglected, Rare, and Commercial Diseases

Barry Bunin, Ph.D., CEO, Collaborative Drug Discovery

Collaborative innovation is uniquely able to realize the economics of well-integrated specialization required for chemical biology and drug discovery. Recent results shared publicly for Neglected Disease applications amply demonstrate these bold suppositions are true and general. Since collaborative technology is “therapeutic area agnostic” it has general been proven equally applicable for commercial applications.

3:45 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

4:25 Kratom-derived Orally Active Analgesic with G-protein Biased mu-Opioid Agonism and delta-Opioid Antagonism

Susruta Majumdar, Ph.D., Assistant Attending, Department of Neurology, Memorial Sloan-Kettering Cancer Center

Mitragynine pseudoindoxyl (MP), a kratom-derived alkaloid is a G-protein biased mu opioid agonist with delta antagonist. It is a potent analgesic in mice, which exhibited no reward, attenuated respiratory depression, and constipation compared to morphine similar to most G-protein biased mu agonists. In addition, MP showed slower development of tolerance and minimal physical dependence owing to its delta antagonism. It is the first molecule engaging two pathways namely G-protein mu opioid biased agonism and delta antagonism.

4:55 Mutation-Guided Unbiased Modeling of the Fat Sensor GPR119 for High-Yield Agonist Screening

Thomas M.Frimurer, Ph.D., Associate Professor, The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark

Recent assessment studies have demonstrated difficulties in accurate modeling of receptor-ligand complexes. We present an unbiased mutation-guided protein-ligand optimization protocol with full ligand and receptor flexibility, which in contrast to conventional derived models could explain SAR and proved successful in separating active ligands from decoys in large-scale virtual screening - directly related to drug discovery applications when applied to the fat censor GPR119 as a case study.

5:25 Welcome Reception in the Exhibit Hall with Poster Viewing

6:25 End of Day

Day 1 | Day 2 | Download Brochure

Wednesday, September 21

7:30 am Registration Open and Morning Coffee


8:00 Chairperson’s Opening Remarks

Adam Weinglass, Ph.D., Director, Cell Pharmacology, In Vitro Pharmacology, Merck Research Laboratories

8:10 Revealing the Structural Basis for GPCR Drug Action through Atomic-Level Simulation

Ron Dror, Ph.D., Associate Professor of Computer Science and, by courtesy, Molecular and Cellular Physiology, Stanford University

We have used molecular dynamics simulations to capture in atomic detail the processes by which drugs bind to GPCRs, by which GPCRs transition between active and inactive states, and by which GPCRs stimulate G proteins. Our results, together with complementary experimental data, suggest opportunities for the design of drugs that achieve greater specificity and control receptor signaling more precisely.

8:40 Negative Allosteric Modulators of the LPA1 Receptor: Using Backscattering Interferometry to Probe Compound Binding

Jonathan Ellery, Ph.D., Director, Pharmacology, Takeda

The LPA1 receptor has attracted considerable interest as a drug target for the treatment of a range of fibrotic conditions. Several pharmaceutical companies have progressed compounds into the clinic. Here we investigate two compounds that have advanced into the clinic alongside a Takeda compound and show evidence to suggest that one is an orthosteric antagonist whilst the others act as negative allosteric modulators.

9:10 PANEL DISCUSSION: Phenotypic v. Target-Based Screening for GPCRs

Moderator: Andrew Alt, Ph.D., Senior Research Investigator, Lead Discovery, Bristol-Myers Squibb


Samantha J. Allen, Ph.D., Senior Scientist, Emerging Science& Innovation, Janssen Research Labs
Laura M. Bohn, Ph.D., Professor, Departments of Molecular Therapeutics & Neuroscience, The Scripps Research Institute
Jonathan Ellery, Ph.D., Director, Pharmacology, Takeda

Adam Weinglass, Ph.D., Director, Cell Pharmacology, In Vitro Pharmacology, Merck Research Laboratories

• Rationale for phenotypic v. target-based screening approaches

• Native v. recombinantly expressed receptor systems for target-based screening

• “But what will we miss?” - case studies

• Deconvolution strategies for phenotypic screening hits

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

10:25 Probing the Functional and Therapeutic Significance of GPCR Oligomerization at the Nano-Scale via Super-Resolution Imaging

Aylin Hanyaloglu, Ph.D., Senior Lecturer, Institute of Reproductive and Developmental Biology, Imperial College London

Organization of GPCRs into dimers and oligomers represents a key mechanism in pleiotropic signaling and has received significant attention for its ability to impact receptor pharmacology and signaling in vivo. Our latest application of super-resolution imaging approaches has unveiled the molecular intricacies of GPCR oligomers and how it defines receptor activity that, in turn, may pave the way for novel avenues in intelligent drug design.

10:55 GPCR Drug Discovery at the Single Molecule Level

Tim Kaminski, Ph.D., Postdoctoral Fellow, Biophysics/Discovery Sciences, AstraZeneca

I am converting single molecule microscopy, a method primarily used in academia, into a versatile tool for drug discovery. We aim to address shortcomings of established biophysical methods such as tight binding limit, working with GPCRs and higher throughput. Additionally we are able to extract kinetic profiling of inhibition reactions in solution by observing the association and dissociation of thousands of molecules in parallel with a surface-based single molecule platform.

11:25 Enjoy Lunch on Your Own

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

3:20 End of Conference

Day 1 | Day 2 | Download Brochure

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