Bi-directional, iterative approach to the structural determination of the binding site of anti-diabetic drugs at GPR40

COMP 206

Irina Tikhonova, tikhonovai@niddk.nih.gov1, Chi Shing Sum, sumchi@niddk.nih.gov2, John Childress, childressj@niddk.nih.gov2, Susanne Neumann, SusanneN@intra.niddk.nih.gov2, Craig J. Thomas, craigt@nhgri.nih.gov3, Bruce M. Raaka, Raaka@intra.niddk.nih.gov2, Stefano Costanzi, stefanoc@intra.niddk.nih.gov1, and Marvin C. Gershengorn, marving@mail.nih.gov2. (1) Computational Chemistry Core Laboratory, NIDDK, National Institutes of Health, 12A Center Drive Rm 4051 MSC 5646, Bethesda, MD 20892-0810, (2) NIDDK Clinical Endocrinology Branch, National Institutes of Health, Bldg 50 Room 4133, 9000 Rockville Pike, Bethesda, MD 20892, (3) NIH Chemical Genomics Center, NHGRI, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850
GPR40 is a G-protein-coupled receptor (GPCR) and a potential target for the treatment of type 2 diabetes. In this work, integrated computational studies including phylogenetic and chemogenetic analyses, homology-based modeling, molecular dynamics simulation, ligand-protein pharmacophore analysis, and automated flexible docking were performed aimed at delineating the ligand binding site of GPR40 and identifying potential ligands. Several key residues for the ligand binding were proposed and experimentally validated by site-directed mutagenesis. Following analysis of the proposed binding cavity and the structures of docked compounds (fatty acids and synthetic agonists), new analogs are suggested with potentially higher affinity for the receptor using de novo design and virtual screening techniques. These data provide the first reported attempt of structural studies of the ligand binding site of GPR40.
 

Poster Session
6:00 PM-8:00 PM, Tuesday, 12 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Computers in Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006