Molecular modeling aided design of nicotinic acid receptor GPR109A agonists

A homology model of the nicotinic acid receptor GPR109A was constructed based on the X-ray crystal structure of bovine rhodopsin. An HTS hit was docked into the homology model. Characterization of the binding pocket by a grid-based surface calculation of the docking model suggested that a larger hydrophobic body plus a polar tail would improve interaction between the ligand and the receptor. The designed compounds were synthesized, and showed significantly improved binding affinity and activation of GPR109A.

Graphical abstractApplication of molecular modeling to aid development of potent GPR109A agonists.Figure optionsDownload full-size imageDownload as PowerPoint slide