Molecular docking and molecular dynamics simulation studies of GPR40 receptor–agonist interactions

In order to explore the agonistic activity of small-molecule agonists to GPR40, AutoDock and GROMACS software were used for docking and molecular dynamics studies. A molecular docking of eight structurally diverse agonists (six carboxylic acids (CAs) agonist, and two non-carboxylic acids (non-CAs) agonist) was performed and the differences in their binding modes were investigated. Moreover, a good linear relationship based on the predicted binding affinities (pKi) determined by using AutoDock and experimental activity values (pEC50) was obtained. Then, the 10 ns molecular dynamics (MD) simulations of three obtained ligand–receptor complexes embedded into the phospholipid bilayer were carried out. The position fluctuations of the ligands located inside the transmembrane domain were explored, and the stable binding modes of the three studied agonists were determined. Furthermore, the residue-based decomposition of interaction energies in three systems identified several critical residues for ligand binding.