J. Med. Chem., 50 (13), 2981 -2989, 2007. 10.1021/jm0614782 S0022-2623(06)01478-6
Web Release Date: June 7, 2007

Not subject to U.S. Copyright. Published 2007 American Chemical Society

Bidirectional, Iterative Approach to the Structural Delineation of the Functional "Chemoprint" in GPR40 for Agonist Recognition

Irina G. Tikhonova, Chi Shing Sum, Susanne Neumann, Craig J. Thomas, Bruce M. Raaka, Stefano Costanzi,* and Marvin C. Gershengorn*

Laboratory of Biological Modeling, Clinical Endocrinology Branch, Chemical Biology Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Received December 26, 2006

Abstract:

GPR40, free fatty acid receptor 1 (FFAR1), is a member of the GPCR superfamily and a possible target for the treatment of type 2 diabetes. In this work, we conducted a bidirectional iterative investigation, including computational modeling and site-directed mutagenesis, aimed at delineating amino acid residues forming the functional "chemoprint" of GPR40 for agonist recognition. The computational and experimental studies revolved around the recognition of the potent synthetic agonist GW9508. Our experimentally supported model suggested that H137(4.56), R183(5.39), N244(6.55), and R258(7.35) are directly involved in interactions with the ligand. We have proposed a polarized NH- interaction between H137(4.56) and GW9508 as one of the contributing forces leading to the high potency of GW9508. The modeling approach presented in this work provides a general strategy for the exploration of receptor-ligand interactions in G-protein coupled receptors beginning prior to acquisition of experimental data.

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