GPCR-Based Drug Discovery Conference 1 header

About This Conference:

The renewed excitement in the field of GPCR drug discovery is due to technological progress which has enabled the collection of more structural data on GPCRs and is allowing study of receptors in different conformational states. This meeting will focus on structural aspects of GPCRs and new assays and technologies whose applications may enable the discovery of more selective and therefore therapeutically attractive modulators of GPCR signaling.


Wednesday, October 8

7:00 am Registration and Morning Coffee


8:05 Chairperson’s Opening Remarks

Donovan Chin, Ph.D., Senior Investigator I, Novartis Institute for Biomedical Research

8:15 FEATURED PRESENTATION: Function and Pharmacology of Class A GPCR: New structural and Computational Insights

Vsevolod KatritchVsevolod (Seva) Katritch, Ph.D., Assistant Professor, Integrative Structural and Computational Biology, The Scripps Research Institute

Class A G protein-coupled receptors represent the largest and the most evolutionary dynamic branch of the GPCR tree. This talk will describe the amazing diversity and the common features of Class A GPCR functional mechanisms emerging from recent crystallographic, spectroscopic and molecular modeling studies of the receptors. Direct applications of this atomic-level knowledge to GPCR pharmacology and drug discovery will be discussed.

9:00 Insights into Activation and Allosteric Modulation of a Muscarinic Acetylcholine Receptor

Andrew C. Kruse, Ph.D., Assistant Professor, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

G protein-coupled receptor (GPCR) signaling plays a central role in most aspects of human physiology, and can be regulated by a wide variety of small molecule drugs. We studied the muscarinic acetylcholine receptors as prototypical GPCRs, and solved structures of these receptors in both inactive and active conformations, as well as bound to a drug-like allosteric modulator. Taken together, these studies shed light on GPCR activation and the regulation of GPCR signaling by allosteric ligands.

9:30 The Human Glucagon Receptor Structure

Fai Siu, Ph.D., Investigator II, Center for Proteomic Chemistry, Novartis Institute for BioMedical Research

Binding of glucagon to the glucagon receptor (GCGR) triggers the release of glucose from the liver during fasting; thus GCGR is important in glucose homeostasis. I will present the crystal structure of the transmembrane domain of human GCGR at 3.4 Å resolution, complemented by extensive site-specific mutagenesis, and a hybrid model of glucagon bound.

10:00 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:45 Structure of a Class C GPCR 7TM Domain and Its Allosteric Modulation

Huixian Wu, Ph.D., formerly Raymond C. Stevens Lab, now Postdoctoral Associate, Center for the Science of Therapeutics, The Broad Institute of MIT and Harvard

The metabotropic glutamate receptors (mGlus), which are class C GPCRs, mediate the modulatory effects of the excitatory neurotransmitter, glutamate. Allosteric modulators of mGlus are important drug candidates for many diseases such as brain disorders. In this talk, the structure of mGlu1 seven-transmembrane domain bound by a negative allosteric modulator will be presented and the structural basis of the allosteric modulation will be discussed.

11:15 Computational Design of Water Soluble Variants of GPCRs and other Membrane Proteins

Jeffery G. Saven, Ph.D., Professor, Department of Chemistry, University of Pennsylvania

Obtaining G-protein coupled receptors (GPCRs) in forms that retain native structural and functional properties remains a core problem of membrane protein science. Membrane proteins can be computationally redesigned, however, to facilitate heterologous expression in E. coli and characterization. We have developed and applied such methods to ion channels and to the human mu opioid receptor, the GPCR target of many pain medications.

11:45 Structural Insights into  Allosteric Agonist Bound Human GPR40 Receptor

Ankita Srivastava, Ph.D., Senior Scientist, SB & Ab Core Science & Technology, Takeda California

Human GPR40 receptor (hGPR40) GPCR  binds to free fatty acids and mediate the insulin secretion in a glucose dependent manner. This unique mode of action of the receptor makes it a promising therapeutic target for Type II diabetes mellitus treatment. I will discuss the crystal structure of hGPR40 bound to its allosteric agonist TAK-875. The structure not only reveals the unique binding mode of the ligand but also provides the insight into the plausible binding of multiple ligands which has already been reported by biochemical studies.

12:15 pm Late Breaking Presentation 

12:45 Session Break

1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:40 Session Break


1:50 Chairperson’s Opening Remarks

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

2:00 Exploration of Drug Disease-Related Selectivity Using Molecular Simulations of the Bioamine Receptor Family

Irina Tikhonova, Ph.D., Lecturer in Molecular Modeling, School of Pharmacy, Queen’s University Belfast

Selective polypharmacology is when drugs act on multiple rather than single molecular targets involved in a disease. We focus on bioamine receptors that are targets for schizophrenia and depression. Among them, 5-HT2A, 5-HT6, D2 and D3 receptors induce cognition-enhancing effects, while H1, 5-HT2C and 5-HT2B receptors causes side effects. A computational dynamic structure-based approach will be presented to identify drugs targeting preferably the disease-active receptors.

2:30 Application of Free Energy Perturbation to GPCR Targets
Woody Sherman, Ph.D., Vice President, Applications Science, Shrödinger Inc
Free energy perturbation (FEP) calculations offer an attractive approach to predicting binding free energies by more accurately accounting for important aspects of binding (e.g. entropy, water networks, and receptor reorganization) that are typically neglected in molecular modeling approaches. However, the application of FEP to GPCRs has been limited due to the challenges associated with running these calculations. We have run FEP on several GPCRs to predict binding affinities for different ligand series and obtained encouraging results. Here, we discuss the FEP method, applications to GPCRs, and future work we are doing to further improve the method.  

3:00 Impact and Gaps in Structural-Based GPCR Drug Discovery: Q&A Panel Discussion

Moderator: Woody Sherman, Ph.D., Vice President, Applications Science, Shrödinger Inc 

Panelists: Donovan Chin/Novartis; Seva Katritch/Scripps; Andrew Kruse/Harvard; Huixian Wu/The Broad Institute; Ankita Srivastava/Takeda

  • Impact on computational chemistry
  • Influence in collaborative culture: interactions between biologists, structural biologists, computational chemists and medicinal chemists?
  • Changing landscapes in assay techniques
  • Evolving skill sets of computational chemists and modelers

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

4:10 The Secrets in Their Landscapes: Using ‘Google Exacyle’ to Elucidate Activation Mechanism of GPCRs for Selective Drug Design

Diwakar Shukla, Ph.D., Simbios Distinguished Fellow, Laboratory of Vijay Pande, Chemistry Department, Stanford University and soon to be Professor, Chemical Engineering, University of Illinois at Urbana-Champaign

Mechanistic understanding of GPCR activation could be obtained via in silico approaches, although this is very challenging due to the long activation timescales. Here, we employ a novel computational paradigm that couples cloud computing and Markov state model based sampling algorithms for mapping the conformational landscape of β2-adrenergic receptor. These computations provide the atomistic picture of activation and help identify key structural intermediates for drug design.

4:40 Free Energies from a Molecular Printing Press

Kenneth M. Merz, Jr., Director, Institute for Cyber Enabled Research (iCER) and Joseph Zichis Chair in Chemistry, Department of Chemistry, Department of Biochemistry and Molecular Biology, Michigan State University

Docking calculations coupled with binding free energy estimates are a mainstay of structure-based drug design. Docking and scoring methods have steadily improved over the years, but remain challenging because of the extensive sampling that is required, the need for accurate scoring functions and challenges encountered in accurately estimating entropy effects. We developed the Moveable Type (MT) method that combines knowledge-based approaches with physics-based models to create molecular ensembles.

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.

Biosensors for GPCRs

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

• Resonance energy transfer technologies
• Label-free biosensor systems
• Use of biosensors to investigate biased signaling

High-Throughput Screening and High-Content Imaging in GPCR Drug Discovery

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

• High-content imaging and its place in lead discovery
• Studying receptor internalization and trafficking
• New HTS approaches

Molecular Dynamics and Simulations of GPCRs

Irina Tikhonova, Ph.D., Lecturer in Molecular Modeling, School of Pharmacy, Queen’s University Belfast

• Examples where simulation knowledge is being applied
• Equilibrium v. non-equilibrium simulations
• Challenges in the field (or how best to integrate knowledge from different sources)

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

7:15 Close of Day

Thursday, October 9

7:30 am Registration and Morning Coffee


8:00 Chairperson’s Opening Remarks

Michel Bouvier, Ph.D., Professeur, Department of Biochemistry, University of Montréal

8:10 Nanobody-Enabled Fragment Screening on Active-State Constrained GPCRs

Jan Steyaert, Ph.D., Director, Structural Biology Brussels Research Center, Vrije University Brussels

Nanobodies are effective tools for stabilizing agonist-bound active states of GPCRs. Building on this technology, we have developed a nanobody-enabled fragment screening approach to explore new chemical space for the development of drugs targeting GPCRs. Our approach has the advantage over other methods in that we can screen fragments that exclusively bind to particular functional conformations of the receptor, allowing us to triage our fragments according to efficacy profile and potency from a single biophysical assay.

8:40 BRET to Study Receptor Pharmacology

Kevin Pfleger, Ph.D., Harry Perkins Institute of Medical Research, Australia

Exciting advances have been made recently with respect to the development of bioluminescence resonance energy transfer (BRET) for studying GPCRs. This includes the validation of the latest BRET reagents and new BRET-based approaches to study all facets of GPCR pharmacology, from ligand binding and G protein-coupling to arrestin recruitment and intracellular trafficking, particularly in terms of heteromeric complexes.

9:10 The Use of Backscattering Interferometry to Investigate Positive Allosteric Modulators of the M4 Receptor

Jonathan Ellery, Ph.D., Principal Scientist, Takeda Cambridge Ltd
Evidence suggests that the activation of the muscarinic acetycholine receptors (mAChRs) in the central nervous system (CNS) may have therapeutic benefit in the treatment of a number of CNS disorders. The use of non-selective agonists is limited due to un-desirable peripheral side effects. One approach to overcome this issue is to identify compounds that selectively positively modulate the M4 mAChR subtype via an allosteric binding site. Here we describe the use of backscattering interferometry, a label free assay technology, to investigate the nature of modulator binding and its co-operative effects upon the binding of the natural ligand acetylcholine to the M4 mAChR. 

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

10:30 Designing Ligands that Specifically Target Nuclear GPCRs

Terry Hébert, Ph.D., Professor, Department of Pharmacology and Therapeutics, McGill University

An increasing number of GPCRs have been demonstrated to be targeted to the endomembrane locations as have their associated signalling cascades. What if half the drugs we deliver reach the wrong intracellular target? What if the target is an intracellular GPCR rather than the better-characterized cell surface version? Caging ligands may be an excellent means of further stratifying the phenotypic effects of known pharmacophores.

11:00 Targeting Dopamine Receptors with Biased Agonists

John A. Allen, Ph.D., Principal Scientist, Neuroscience, Pfizer

11:30 Enjoy Lunch on Your Own

1:00 pm Plenary Keynote Program 

Chas BountraChas Bountra, Ph.D., Professor of Translational Medicine & Head, Structural Genomics Consortium, University of Oxford

Martin TolarMartin Tolar, M.D., Ph.D., Founder, President & CEO, Alzheon, Inc.

Andrew L. Hopkins, Andrew L. Hopkins, D.Phil, FRSC, FSB, Chair of Medicinal Informatics and SULSA Research Professor of Translational Biology, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee

2:45 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Close of Conference

Suggested Event Package:

October 7

*Short Course: GPCR Structure-Based Drug Discovery 

*Short Course: Targeting of GPCRs with Monoclonal Antibodies 

October 8-9: GPCR-Based Drug Discovery Conference 

October 9-10: GPCR-Targeted Therapeutics Conference 

October 9

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

*Separate registration is required

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The exhibit hall was sold out in 2013, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2014, contact:

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