Insight into the binding modes and inhibition mechanisms of adamantyl-based 1,3-disubstituted urea inhibitors in the active site of the human soluble epoxide hydrolase

Soluble epoxide hydrolase (sEH) is a promising new target for treating hypertension and inflammation. Considerable efforts have been devoted to develop novel inhibitors. In this study, the binding modes and interaction mechanisms of a series of adamantyl-based 1,3-disubstituted urea inhibitors were investigated by molecular docking, molecular dynamics simulations, binding free energy calculations, and binding energy decomposition analysis. Based on binding affinity, the most favorable binding mode was determined for each inhibitor. The calculation results indicate that the total binding free energy (ΔG_TOT, the sum of enthalpy ΔG_MM-GB/SA, and entropy −TΔS) presents a good correlation with the experimental inhibitory activity (IC₅₀, r² = .99). The van der Waals energy contributes most to the total binding free energy (ΔG_TOT). A detailed discussion on the interactions between inhibitors and those residues located in the active pocket is made based on hydrogen bond and binding modes analysis. According to binding energy decomposition, the residues Asp333 and Trp334 contribute the most to binding free energy in all systems. Furthermore, Hip523 plays a major role in determining this class of inhibitor-binding orientations. Combined with the results of hydrogen bond analysis and binding free energy, we believe that the conserved hydrogen bonds play a role only in anchoring the inhibitors to the exact site for binding and the number of hydrogen bonds may not directly relate to the binding free energy. The results we obtained will provide valuable information for the design of high potency sEH inhibitors.