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

Shaoyong Lu, Yongjun Jiang, Jing Lv, Tianxing Wu, Qingsen Yu, Weiliang Zhu

A B S T R A C T

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 bindingmodes 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.