Insight into analysis of interactions of GW9508 to wild-type and H86F and H137F GPR40: A combined QM/MM study and pharmacophore modeling

GPR40 is a novel potential target for the treatment of type 2 diabetes. In this work, a two-layered ONIOM based QM/MM approach was employed to study the interactions between GW9508 and GPR40: wild-type, H86F, and H137F mutated systems. The calculated results clearly indicated that His137 is directly involved in ligand recognition through the NH–π interaction with the GW9508. In contrast, His86 is not interacting with the GW9508 in the NH–π interaction. The interaction energies, calculated at the MP2/6–31(d, p) level, were performed to gain more insight into the energetic differences of the wild-type and two mutated systems at the atomistic level. In addition, the obtained pharmacophore model was well consistent with structure–functional requirements for the binding of GPR40 agonists and with per-residue energy decomposition of the ONIOM calculations.

Graphical abstractTwo-layer ONIOM calculations were applied to investigate the binding modes of GW9508 to the GPR40 binding pocket of wild-type, H86F, and H137F mutant systems involving the NH–π interaction.Figure optionsDownload full-size imageDownload high-quality image (75 K)Download as PowerPoint slideResearch highlights► A two-layered ONIOM approach was employed to study the interactions between GW9508 and GPR40. ► The energetic differences of the wild-type and two mutated systems were studied. ► A pharmacophore model was well consistent with the ONIOM calculations.