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

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−π 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.