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Day 1 - G Protein-Coupled Receptor Drug Discovery

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Tuesday, April 29th

12:30 pm Registration

GPCR STRUCTURE AND MECHANISM

1:30 Chairperson’s Opening Remarks
Graeme Milligan, Ph.D., Professor of Molecular Pharmacology, University of Glasgow

1:40 Crystal Structures of the Human Beta2-Adrenergic G Protein-Coupled Receptor
Daniel Rosenbaum, Ph.D., Kobilka Lab, Department of Molecular and Cellular Physiology, Stanford University
We have solved the high-resolution structure of an inverse agonist-bound beta2 adrenergic receptor by X-ray crystallography, enabled by protein engineering and lipid-mediated crystallization methods. This structure represents the first molecular picture of a GPCR recognizing a diffusible ligand, and allows for comparison with previous structures of rhodopsin. Furthermore, the structure provides a molecular basis for understanding ß2AR pharmacology, and is a crucial step toward elucidating the mechanism of ligand-induced conformational change in this prototypical Class A GPCR.

2:10 Novel Chemotypes to Melanin-Concentrating Hormone Receptor 1 Discovered Through Ligand-Steered Homology Modeling and Virtual Screening
Claudio Cavasotto, Ph.D., Professor, School of Health Information Sciences, University of Texas Health Science Center at Houston
Melanin-concentrating hormone receptor 1 belongs to the Class A of G protein-coupled receptors. It is involved in feeding and energy balance, and thus constitutes an attractive target for antiobesity therapy. However, the discovery of novel antagonist chemotypes through structure-based virtual screening is hampered by the lack of an available experimental structure. A ligand-steered homology modeling method was developed, where the information about existing antagonists is incorporated directly into the modeling of the binding pocket. The models thus generated were used in virtual screening of circa 200,000 compounds. Of the 129 top-scoring compounds, six were found to be active in the low-micromolar range. This performance was found to be 10-fold better than high-throughput screening. 

2:40 In Silico Screening and Structure-Based Design for Lead Finding and Optimization
Sid Topiol, Ph.D., Associate Director, Computational Chemistry Department, Lundbeck Research USA
Approaches to in silico drug design for soluble proteins are becoming straightforward, albeit non-trivial. For GPCR targets, structure-based approaches are a new frontier. The recently reported X-ray structure of the β2-adrenergic receptor, the first available crystal structure of a ligand-mediated GPCR, is used to explore its utility in computer-aided drug design. We demonstrate that such approaches are able to provide valuable results for lead finding, optimization, and novel template identification, particularly when coupled to a broad platform of ligand-based approaches. 

3:10 Technology Watch (Sponsorship Available)

3:25 Networking Refreshment Break, Poster and Exhibit Viewing

4:05  Endogenous Agonist Mechanism for Activation of Class II GPCRs
Laurence Miller, M.D., Research, Mayo Clinic
The structurally unique and characteristic amino-terminal region of Class II G protein-coupled receptors is critically important for ligand binding and receptor activation.
Understanding the precise role it plays requires clear insight into the molecular basis of its ligand interactions and the conformation of the ligand-receptor complex. We have studied these features of the prototypic secretic receptor. For this, we have used affinity labeling with secretin-like photolabile probes with sites for covalent attachment spanning the pharmacophore. We have utilized sequential proteolysis and sequencing of the labeled regions of the receptor to identify specific spatial approximation constraints. Additionally, we have utilized fluorescence approaches to analyze microdomains of the docked ligand and to measure distances from ligand to specific sites within the receptor. All of these experimentally derived constraints have been used to establish and refine a working model of the ligand-docked receptor. Further, dynamic changes in conformation were explored to gain insights into mechanisms of activation of this receptor. This has resulted in a unique working hypothesis of an endogenous agonist mechanism, whereby this region of the amino terminus is exposed upon ligand binding and interacts with the receptor core domain. Alternate mechanisms of activation will be explored.

ALLOSTERIC MODULATORS OF GPCRs

4:35 In Vitro and In Vivo Characterization of Highly Subtype-Selective Allosteric Modulators of the M1 and M4 Muscarinic Receptors
Craig W. Lindsley, Ph.D., Department of Pharmacology & Chemistry, Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center
M1 and M4 mAChR subtypes of the muscarinic receptor represent attractive targets for many CNS disorders including Alzheimer’s disease (AD) and Schizophrenia. Traditional muscarinic agonists lack efficacy and carry severe side effects due to non-selective activation of all mAChR subtypes, and absence of selective agents has hindered basic research into the respective roles of the M1 and M4 receptors in the CNS. We report the discovery and preliminary characterization of novel muscarinic ligands that modulate either the M1 or M4 receptor in an allosteric manner with high subtype-selectivity. We also report the discovery of a highly potent M1 antagonist with unprecedented selectivity. Functional cell-based HTS and technology-enabled synthetic methods were used to identify and optimize a number of compounds. An identified allosteric agonist, TBPB, demonstrated disease modification potential for AD by decreasing Aβ secretion in an APP processing assay. TBPB also displayed in vivo antipsychotic activity in rodent studies. A novel series of centrally active M4 positive allosteric modulators have demonstrated antipsychotic efficacy in preclinical models.

5:05 ADX47273, A Novel Positive Allosteric Modulator of Metabotropic Glutamate Receptor 5 with Antipsychotic-Like and Cognitive-Enhancing Effects in Rodents
Emmanuel Le Poul, Ph.D., Head of CNS Business Unit, Addex Pharmaceuticals
mGluR5 PAMs may represent a novel class of therapeutics for the treatment of schizophrenia and central nervous system disorders characterized by cognitive dysfunction. We report here the discovery and the extended characterization of a novel mGluR5 PAM, ADX47273, which is potent and selective on mGluR5, with oral bioavailability, pharmacokinetic properties, and brain penetration suitable for testing in preclinical models of psychosis and cognition.

5:35 End of Day 


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