GPR119 is a G protein-coupled receptor shown to be important for the treatments of Type 2 diabetes. Understanding how the receptor works is essential for drug development. One of the tools to study receptors are inverse agonists; these are compounds that bind to the receptor and prevent it from activating. To date few inverse agonists of the GPR119 receptor have been reported in the literature and it is not known how they interact with it. The goal of this project is to study the structure of two different inverse agonists and their mode of binding to the GPR119 receptor. The Schrodinger Molecular Modeling software was used to explore the conformational space of two inverse agonists, AR436352 (long and slender shape) and TM43718 (shorter and wider shape). A conformational search followed by quantum mechanical optimizations was run to locate the global energy minimum conformers of the two molecules as well as other low energy structures and to calculate the electron density distribution of the global energy minimum conformers. The electron density map of the inverse agonists was compared to the electron density map of the binding site to provide insight on how the molecules may fit inside the receptor binding pocket. The program Glide was used to dock the two molecules in the GPR119 receptor binding site. The docked complexes were minimized using a QM/MM method. The docking results indicate that the inverse agonists bind in between the transmembrane helices 2, 3, 6, and 7. One end of the molecule extends to the extracellular loop region and the other end is situated above the toggle switch amino acid W6.48 preventing it from moving. The interaction energies between the binding side amino acids and the inverse agonists were calculated. The analysis suggests that amino acids W7.39, F6.51, T3.33, M3.29, R3.28, as well as the extracellular loop 2 amino acid F157 are important for binding. Site directed mutagenesis will be used to confirm these results.

Exploring the binding site of GPR119 receptor inverse agonists

253rd National Meeting (2017)

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