Examining the potency of suggested inhibitors for the phosphatase activity of the human soluble epoxide hydrolase by molecular dynamics simulations

The N-terminal domain of human soluble epoxide hydrolase (EH) has been recently reported as phosphatase. In this work, molecular dynamics (MD) simulations were performed to study the binding modes of three inhibitors (A, B and C, Scheme 1) of the phosphatase activity. Recently, compound A has been tested as inhibitor of the phosphatase activity of the EH enzyme with IC₅₀ = 0.84 μM. Results reveal that the hydrophobic tail of each inhibitor resides in the hydrophobic cleft of the N-terminal domain while the polar head interacts with the Mg²⁺-aspertate active site and the nearby polar and charged amino acid residues. The obtained MD trajectories were analyzed to study and discuss the hydrogen bonds formed between enzyme and each inhibitor and the role of Mg²⁺ ion in recognition. MM-PBSA method was used to estimate the binding free energy of each EH/inhibitor complex. Results indicate that guest-host electrostatic interactions have the largest contribution to the complex stability. Also, a significant contribution of van der Waals interactions was found. The suggested inhibitor (B) exhibits much higher affinity toward the enzyme compared to the experimentally tested inhibitor A.