Dynamic Simulation Studies On The Interactions Between Human Soluble Epoxide Hydrolase And Inhibitors

Protein-ligand interactions are the basis of all the biochemical processes in living systems. A deep understanding of protein-small molecule interactions is of great interest as it provides opportunities for understanding function and therapeutic intervention. It will cause a profound impact on molecular recognition and drug molecules design.We employed a method combined with molecular docking and molecular dynamics simulations to study the interaction of human epoxide hydrolase with amide and urea inhibitors in current thesis.(1) Probing Ligand-binding modes and binding mechanisms of benzoxazole-based amide inhibitors with soluble Epoxide Hydrolase by molecular docking and molecular dynamics simulation.Soluble epoxide hydrolase (sEH) has become a new therapeutic target for treating a variety of human diseases. The inhibition of human sEH hydrolase activity was studied by molecular docking and molecular dynamics (MD) simulation techniques. A set of six benzoxazole-based amide inhibitors binding to sEH has been studied through molecular docking, MD simulation, free energy calculations, and energy decomposition analysis. On the basis of molecular mechanics-generalized Born/surface area (MM-GB/SA) computation and normal mode analysis (NMA), the obtained results indicate that the rank of calculated binding free energies (ΔΔGTOT) of these inhibitors is in excellent agreement with that of experimental bioactivity data (IC50). The correlation coefficient (r2) between the predicted ΔΔGTOT and IC50is0.88. van der Waals energies are the largest component of the total energies and the entropy changes play an indispensable role in determining the ΔΔGTOT.Rational binding modes were discussed and determined by the docking results and binding free energies. The free energy decomposition of each residue reveals that the residue Trp334dominates the most binding free energies among all residues and the activities for these molecules to the sEH are not decided by hydrogen bonds or a certain residue but by the common effect of multiple side chains in the active site.(2) Insight into the Binding Modes and Inhibition Mechanisms of Adamantyl-based1,3-disubstituted Urea Inhibitors in the Active Site of the Human Soluble Epoxide Hydrolase.The binding modes and interaction mechanisms of a series of adamantyl-based1,3-disubstituted urea inhibitors were investigated by combining molecular docking, molecular dynamics simulations, binding free energy calculations, and binding energy decomposition analysis. Based on binding affinity, those favorable binding modes had been determined. The binding free energy calculations indicated that the total binding free energies present a good correlation with the experimental inhibitory activity (IC50, r2=0.99). van der Waals energies are the largest component contributed to the total energies. The electrostatic energies are the major reasons for distinct binding affinity in different binding modes. A detailed discussion of the interaction mechanisms of inhibitors with residues in the active pocket was made based on hydrogen bond and binding modes analysis. According to binding energy decomposition, the residues Asp333and Trp334contributed the most binding free energies in all systems. Furthermore, Hip523play a major role in determining this class of inhibitor-binding orientations. These obtained results in this works will provide valuable information for the design of high potency sEH inhibitors in the future.