Investigation of the binding mode of 1, 3, 4-oxadiazole derivatives as amide-based inhibitors for soluble epoxide hydrolase (sEH) by molecular docking and MM-GBSA.

The soluble epoxide hydrolase (sEH) enzyme plays an important role in the metabolism of endogenous chemical mediators involved in the regulation of blood pressure and inflammation. Inhibition of sEH provides a new approach to the treatment of inflammation, hypertension and atherosclerosis. In this study, the binding modes and inhibition mechanisms of the new oxadiazole-based amide inhibitors of the human soluble epoxide hydrolase were investigated by molecular docking and molecular dynamics (MD) simulation followed by the MM-GBSA method to calculate the binding free energy of each inhibitor to sEH. The results obtained from the binding free energy (ΔG binding) calculation and normal mode analysis indicate that the major favorable contributors are the van der Waals and electrostatic terms, whereas the polar solvation term opposes binding. In addition, a good agreement between the calculated ΔG binding and the experimental IC50 was obtained [correlation coefficient, r 2 = 0.89 (with) and 0.87 (without) entropy]. Besides, comparison of the enthalpy changes (ΔG MM-GBSA) with entropy changes (-TΔS) indicates that binding process of all inhibitors to sEH is enthalpy-driven. Based on the ΔG binding on per residue decomposition, Asp335 and Tyr383 residues from the active site and Trp336, Leu499 and His524 residues from hydrophobic pockets contribute the most to ΔG binding. Moreover, hydrogen bond analysis reveals that Tyr383, Tyr466 and Asp335 residues have an important role in the binding to inhibitors by forming hydrogen bonds with high occupancies. Our obtained results are useful for the understanding of the sEH-inhibitor interactions and may have great importance in the design of future sEH inhibitors.