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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


STRUCTURAL FEATURES OF GPCRS AND IMPLICATIONS FOR DRUG DESIGN

8:05 Chairperson’s Opening Remarks

Xinjun Hou, Ph.D., Head, Computational Chemistry, Neuroscience Department, Pfizer

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 Structure and Ligand Binding Analysis of a Lipid Receptor

Michael Hanson, Ph.D., Director, Structural Biology, Receptos, Inc.

The Edg family of lipid binding receptors has been widely studied since the discovery of its first member the S1P1 receptor. The structure of the S1P1 receptor has been used to understand the binding mode of pharmaceutical agents for the treatment of relapsing multiple sclerosis. This structure can also be used to understand pharmacological differences within the lipid binding class of G protein coupled receptors.

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., Raymond C. Stevens Lab, Department of Integrative Structural and Computational Biology, The Scripps Research Institute

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 Targeting Dopamine Receptors with Biased Agonists

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

12:45 Session Break

1:00 Luncheon Presentation

Speaker to be Announced

1:40 Session Break


SIMULATIONS AND BIG DATA

1:50 Chairperson’s Opening Remarks

Michael Hanson, Ph.D., Director, Structural Biology, Receptos, Inc.

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

Moderator: Xinjun Hou, Ph.D., Head, Computational Chemistry, Neuroscience Department, Pfizer

  • 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

3:00 Sponsored Presentations (Opportunities Available)

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

GPCR Imaging Applications

Marla Watt, Ph.D., Senior Research Investigator, Purdue Pharma, LP

• Using imaging for secondary high-content screens
• Studying receptor internalization and trafficking
• Pros and cons of various equipment/setups

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


NEW APPROACHES FOR STUDYING GPCRS

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

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 Sponsored Presentation

Speaker to be Announced

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 High-Content Analysis to Study GPCR Internalization and Trafficking

Marla Watt, Ph.D., Senior Research Investigator, Purdue Pharma, LP

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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2014 Discovery on Target Brochure  

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PREMIER SPONSORS 

Cellecta 

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SPONSORSHIPS & EXHIBITS 

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:

Jon Stroup
Business Development Manager
781-972-5483
jstroup@healthtech.com 

2014 Discovery On Target CAG 

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CONFERENCES


October 8 – 9

Targeting Epigenetic Readers and
Chromatin Remodelers
 

Targeting the Ubiquitin Proteasome System  

Big Data Analytics and Solutions  

GPCR-Based Drug Discovery  

RNAi for Functional Genomics Screening
– Part 1
 

Protein-Protein Interactions as Drug Targets  

Antibodies Against Membrane Protein Targets
– Part 1
 


October 9 – 10

Targeting Histone Methyltransferases and Demethylases  

Screening Drug Transporter Proteins  

Maximizing Efficiency in Discovery  

GPCR-Targeted Therapeutics  

Genome Editing for Functional Genomics
Screens – Part 2
 

Cancer Metabolism  

Antibodies Against Membrane Protein Targets
– Part 2
 


SYMPOSIUM


October 7

Next Generation Histone Deacetylase Inhibitors  


SHORT COURSES


October 7

SC1: Designing Scalable Software Systems for Big Data Analytics  

SC2: Approaches for Biologically-Relevant Chemical Diversity  

SC3: Setting Up Effective RNAi Screens: From Design to Data to Validation  

SC4: Targeting Protein-Protein Interactions  

SC5: GPCR Structure-Based Drug Discovery  

SC6: Advances in Metagenomic Drug Discovery for New Anti-Infective Agents  

SC7: Targeting of GPCRs with Monoclonal Antibodies  

SC8: A Primer to Gene Editing: Tools and Applications  

SC9: Introduction to Targeted Covalent Inhibitors  


October 9

SC10: Setting Up Effective Functional Screens Using 3D Cell Cultures  

SC11: Integration of BDDCS and Extended Clearance Principles  

SC12: Introduction to Allosteric Modulators and Biased Ligands of GPCRs  

SC13: Introduction to Drug Metabolism