GPCR-Based Drug Discovery

G protein-coupled receptors (GPCRs), which relay chemical signals such as hormones from outside to the inside of cells, are the targets of approximately a third of the medicines on the market today. However, many of the GPCR-acting medicines were discovered decades or more ago, without today’s more detailed knowledge about and tools for working with GPCRs. The receptors span the membrane seven times, thus are challenging to solubilize and study in vitro. Recent biophysical advances though have bypassed some of the membrane-embedded challenges and enabled GPCR structural insights and spurred new screening applications. The receptors’ signaling complexities due to their ability to couple to a variety of G proteins (biased signaling) are also now more understood and capitalized upon to design more selective drugs. CHI’s well-established GPCR-Based Drug Discovery conference will continue to convene prominent scientists in both academics and industry to share and discuss the latest advances in applied GPCR research ranging from new screening assays and biophysical techniques, to structure-based drug development to medicinal chemistry optimization case studies to examples of GPCR-targeted compounds in development.

Final Agenda

Choose 2 Short Courses
or 1 Symposium and 2 Conferences/Training Seminars

Thursday, September 27

11:50 am Conference Registration Open (Foyer)

12:20 pm Plenary Keynote Program (Constitution Ballroom)

2:00 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

GPCR Structures And Targeted Drug Design Implications
Back Bay B

2:45 Welcome Remarks

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

2:50 Chairperson’s Opening Remarks

Dean G. Brown, PhD, Director of External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca

2:55 Structural Pharmacology of GPCRs in Asthma and Structure-Based Drug Development

Zhang_ChengCheng Zhang, PhD, Assistant Professor, Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine

The commonly used medication for controlling asthma includes bronchodilators and anti-inflammation drugs. Almost all bronchodilators are the agonists of beta2 adrenergic receptor (beta2AR). We report a crystal structure of human beta2AR bound to the most widely used asthma drug salmeterol, which reveals the bitopic nature of salmeterol and an additional ligand binding site in the receptor. The results provide a structural explanation for the prominent pharmacological characteristics of salmeterol including high receptor-subtype selectivity and long-lasting action. We also present the first crystal structures of a lipid GPCR, the CRTH2, as a new target for developing small molecule anti-inflammation drugs for asthma. The structures reveal critical features for the binding of CRTH2 antagonists including a Phase III drug candidate, fevipiprant. They also suggest a novel mechanism for the recognition of endogenous lipid mediators by GPCRs. Based on the structures, we have identified compounds with novel structural scaffolds as potential antagonists of CRTH2, and propose new strategies for further drug development.

3:25 Apelin Receptor Structure and Signaling

Hu_LiaoyuanLiaoyuan Hu, PhD, Scientific Director, Discovery Pharmacology, Amgen Asia R&D Center

Apelin receptor (APJ) plays important roles in a variety of physiological processes such as heart contractility, energy metabolism and fluid homeostatic. We will report APJ high resolution crystal structure and molecular mechanism of receptor activation and signaling selectivity. These results shed light on the understanding of the general mechanism of class A receptor activation and functional selectivity, and will facilitate the rational design of novel therapeutics with improved pharmacokinetic and pharmacodynamics properties.

creoptix 3:55 Biophysical Methods in Drug Discovery Dedicated to Membrane Protein Targets

Michael Hennig, PhD, CEO, leadXpro AG

leadXpro combines high-quality transmembrane protein generation with structure determination methods like X-ray (SwissFEL/SLS) and cryo-EM as well as wave-guided interferometry to characterize molecular interactions with drug targets. Examples will illustrate the high sensitivity of Creoptix’ instruments and the accurate measurement of ligand binding and kinetics to support drug design.

4:10 Complexity Simplified: Using Smart Drug Discovery Software to Manage Disperse Assay Data

Robinhold_Dan_GPCDan Robinhold, Research Informatics, Collaborative Drug Discovery, Inc.

Research of tomorrow is moving quickly toward a more collaborative, open source and platform-independent environment. CDD Vault (Assay Reg/ELN/Viz) now incorporates “BioAssay Express” that utilizes machine learning to scan and catalog libraries of human-readable assay text into computer-readable format to better access private, collaborative and public assay data.

4:25 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

New GPCR-Targeted Assays And Compounds
Back Bay B

5:00 Identification and Optimization of a CGRP Receptor Antagonist of Novel Chemotype

Crowley_B_GPCBrendan Crowley, PhD, Associate Principal Scientist, Neuroscience, Merck Research Labs

I describe our strategy to rapidly evolve a series of CGRP receptor antagonists utilizing physical property, ligand efficiency, and diversity-guided iterative library design as well as evidence that these molecules make novel interactions in the binding site (from receptor mutagenesis, X-ray crystallography, and NMR data). I also discuss lead optimization efforts that led to an advanced candidate with high affinity for the receptor, potent in vivo activity, good off-target selectivity, and a low potential human dose.

5:30 TruPath: An Open-Source Platform for Comprehensive Screening of GPCR Signal Transduction Pathways

Strachan_R_GPCRyan T. Strachan, PhD, Research Assistant Professor, Pharmacology, University of North Carolina – Chapel Hill

Our understanding of G Protein-Coupled Receptor (GPCR) signaling remains incomplete and likely conceals therapeutically useful bias. Here we present an open source, optimized BRET-based Transducer Pathway screening platform (dubbed ‘TruPath’) that measures activation of 18 different G-protein signaling pathways. When combined with our GPCRome library, TruPath enables potency and efficacy profiling for both established (e.g., opioid) and understudied (e.g., MRGPRX2) receptors and their ligands, thereby revealing the full extent of transducer promiscuity and bias. We hope that such a panoramic understanding of GPCR signaling reveals new biology and therapeutic strategies.

6:00 Exploration of Endosomal GPCR Signaling Using Electron Microscopy

Thomsen_AlexAlex Thomsen, PhD, Assistant Professor, Department of Surgery, Columbia University

We recently demonstrated that a class of GPCRs promotes endosomal signaling by forming “megaplexes” composed of a single GPCR that interacts simultaneously with β-arrestin, which drives the receptor internalization, and G protein, which initiates signaling from internalized compartments. Now we are applying a variety of electron microscopy (EM) and computational methods to obtain high-resolution structural information about the megaplex (cryo-EM), and to visualize GPCR signaling on the endosomal surface within living cells.

6:30 Dinner Short Course Registration (Foyer)

9:30 Close of Day

Friday, September 28

7:00 am Registration Open (Foyer)

7:30 Interactive Breakfast Breakout Discussion Groups - View Details

Room: Constitution B

Grab a cup of coffee and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic.

Table 9: New Ways to Screen GPCRs

Moderator: NEW: Brian J. Murphy, PhD, Senior Principal Scientist, Metabolic Disease Biology, Bristol-Myers Squibb Co.

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

Table 10: New technologies for GPCR Structure-Function Insights and Drug Discovery Impact

Moderator: Matthew Eddy, PhD, Assistant Professor, Chemistry, University of Florida

  • XFEL and other crystallography advances
  • NMR applications for drug screening
  • cryoEM: current applications and future directions

Table 11: SMALP/Nanodisc Technology for Membrane Proteins

Moderator: Mahmoud l. Nasr, RPh, PhD, Instructor, Biological Chemistry and Molecular Pharmacology Department. Harvard Medical School

  • Similarities and differences of lipid interactions with SMA (styrene-maleimide polymers) v. MSP (membrane scaffold proteins) nanodiscs
  • Advantages and limitations of SMALP particles and MSP nanodiscs in solution
  • Covalently Circularized Nanodiscs 
  • DNA-Corralled Nanodiscs
  • Possible applications of small and large nanodiscs in biotechnology and medicine
  • Future directions and problems 


Back Bay B

8:30 Chairperson’s Remarks

Lakshmi Devi, PhD, Professor, Department of Pharmacology, Mount Sinai School of Medicine

8:35 FEATURED PRESENTATION: Mu Opioid Receptor Pharmacology: A Window into Another Dimension of GPCR Function

Gavril_PasternakGavril Pasternak, MD, PhD, Chair and Professor of Neurology, Neuroscience, Pharmacology and Psychiatry, Weill Cornell Medical College; Laboratory Head, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center

The mu opioid receptor Oprm1 is a member of the G-protein coupled receptor family. First demonstrated in 1973, it led to the discovery of the endogenous opioids and the ‘sodium effect’ in which sodium ions allosterically transition receptors between agonist and antagonist conformations – now established with most GPCRs. Cloning the receptor uncovered a vast array of Oprm1 splice variants, including an atypical target capable of eliciting analgesia without the side effects associated with classical opioids.

9:05 GPCR Dimerization and Deorphanization: Impact on Drug Discovery

Devi_L_GPCLakshmi Devi, PhD, Professor, Department of Pharmacology, Mount Sinai School of Medicine

Studies in Dr. Lakshmi Devi’s laboratory aim at unraveling the molecular mechanisms of signal transduction mediated by G-protein coupled receptors (GPCRs) and their regulation in health and disease. Recent studies have focused on the identification of compounds targeting opioid receptor heteromers as well as ligands targeting recently deorphanized hypothalamic neuropeptide GPCRs. This presentation will focus on different approaches used in novel ligand identification for the treatment of pain and addiction.

9:35 Mechanisms of Biased Agonist Activation of the Angiotensin Receptor

Wingler_LLaura M. Wingler, PhD, Postdoctoral Researcher, Howard Hughes Medical Institute, Lefkowitz Lab, Department of Medicine, Duke University Medical Center

The angiotensin II type 1 receptor is a premier model system for studies of biased agonism in GPCRs, as it has both Gq-biased and β-arrestin-biased agonists that have been exceptionally well characterized. Here we use multiple structural techniques to elucidate the distinct angiotensin receptor conformations stabilized by functionally diverse ligands. Our findings suggest mechanisms by which biased agonists induce the receptor to couple selectively to particular transducers and achieve their different biological profiles.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced (Grand Ballroom)

Receptor Kinetics And Allosteric Modulation
Back Bay B

10:45 FEATURED PRESENTATION: Receptor Kinetics for Probing Allosteric Modulation and Biased Signaling

Terry_KenakinTerry Kenakin, PhD, Professor, Department of Pharmacology, University of North Carolina School of Medicine

I will compare the muscarinic receptor Gq protein activation profiles of five exemplar molecules (slow binding agonists, partial agonists, inverse agonists, PAM-Agonists and Beta-PAMs) in calcium and IP1 assays to illustrate how quantitative comparisons to pharmacological models can both identify mechanisms of action and also convert descriptive findings to predict data for therapeutic systems. Using these models optimally allows the identification of consistent and simple scales of activity that can guide medicinal chemistry.

11:15 Drug-Target Binding Kinetics - A Case for GPCRs

Guo_D_GPCDong Guo, PhD, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, China

The success rate of a candidate drug moving through the clinical development phase is disappointingly low despite the fact that properties of drug candidates for a given therapeutic target are mostly optimized with respect to standard pharmacological parameters of affinity, potency and intrinsic activity. Determining drug target binding kinetics, next to traditional potency measures, may increase the rate of success. Our work provides new insights in ligand-GPCR interactions and underlines the importance of measuring binding kinetics of both drug candidates and competing endogenous ligands.


11:45 Biortus Delivers Cryo-EM Service to Drug Discovery

Xiaodong Yan, Executive Director, Biology, Biortus

Wuxi Biortus Biosciences Co. Ltd (founded in 2009) is located in Wuxi within the greater Shanghai area of China. As an innovation-driven CRO, Biortus is the first and the only company available in China who delivers the cutting-edge cryo-EM service to drug discovery industry. 

12:15 pm Session Break

Multispan-light 12:25 Luncheon Presentation: Measure β-Arrestin Signaling Through Native GPCRs In High Throughput

Lisa Minor, Scientific Consultant, Business Development, Multispan, Inc.

Screening compounds for biased signaling using native GPCR in one cellular environment may lead to selective perturbation of disease-specific pathways. Our newly developed proprietary MultiScreenTM β-arrestin technology overcomes the receptor-tagging drawback of other existing technologies, enabling high-throughput detection of β-arrestin translocation induced by native GPCRs in vitro and in vivo for the first time. This presentation will highlight these novel features and the robustness of this assay among other updates of our portfolio.

1:15 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

Biophysical Approaches
Back Bay B

1:55 Chairperson’s Remarks

Brian J. Murphy, PhD, Senior Principal Scientist, Metabolic Disease Biology, Bristol-Myers Squibb Co.

2:00 Discovery of Small Molecule Protease-Activated Receptor 2 (PAR2) Antagonists Using a Stabilized GPCR, Fragment-Based Lead Generation and DNA-Encoded Library Screening

Brown_DDean G. Brown, PhD, Director of External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca

We employed two screening strategies to identify antagonists at protease activated receptor (PAR2), one being a DNA-encoded library screen on PAR2 and the second a fragment screen using a stabilized PAR2 GPCR receptor. From these efforts, we identified two lead series of compounds, each of which bind to distinct and previously unknown allosteric sites. These results illustrate the power of integrating stabilized GPCR technologies into established screening paradigms.

2:30 Integrating Biophysical and Structural Data Provides Comprehensive View of GPCR Function

Eddy_MatthewMatthew Eddy, PhD, Assistant Professor, Department of Chemistry, University of Florida and Affiliated Faculty, National High Magnetic Field Laboratory

3:00 NEW: Nanodiscs for Membrane Protein Drug Discovery Applications

Mahmoud l. Nasr, RPh, PhD, Instructor, Biological Chemistry and Molecular Pharmacology Department. Harvard Medical School

We present a method for manufacturing membrane bilayer nanodiscs encircled by DNA scaffold or covalently circularized Apolipoprotein A1 variants. We are able to extend the size of nanodiscs up to 90 nm in diameter. Furthermore, we demonstrate the potential use of these nanodiscs as model membranes to study virus entry. Finally, we demonstrate the potential use of these newly engineered nanodiscs in GPCR and antiviral drug discovery.

3:30 NEW: Close of Conference


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