title: 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.
abstract: 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 (ΔGbinding) 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 ΔGbindingand the experimental IC50was obtained [correlation coefficient, r2= 0.89 (with) and 0.87 (without) entropy]. Besides, comparison of the enthalpy changes (ΔGMM-GBSA) with entropy changes (-TΔS) indicates that binding process of all inhibitors to sEH is enthalpy-driven. Based on the ΔGbindingon per residue decomposition, Asp335 and Tyr383 residues from the active site and Trp336, Leu499 and His524 residues from hydrophobic pockets contribute the most to ΔGbinding. 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.
authors.affiliation: Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.|Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
authors.forename: Leila
authors.initials: L
authors.lastname: Karami
authors.affiliation: Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. saboury@ut.ac.ir.
authors.forename: Ali Akbar
authors.initials: AA
authors.lastname: Saboury
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Elham
authors.initials: E
authors.lastname: Rezaee
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Sayyed Abbas
authors.initials: SA
authors.lastname: Tabatabai
mesh_terms: D000577:Amides / Q000737:chemistry*; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010069:Oxadiazoles / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D004851:Epoxide Hydrolases
keywords: Blood pressure; Inflammation; MM-GBSA; Molecular docking; Molecular dynamics simulation; Soluble epoxide hydrolase