Structural Insight into Binding Mode of 9-Hydroxy Aristolochic Acid, Diclofenac and Indomethacin to PLA₂

Phospholipase A₂ (PLA₂) catalyzes the hydrolysis of phospholipids into arachidonic acid and lysophospholipids. Arachidonic acid is modified by cyclooxygenases into active compounds called eicosanoids that act as signaling molecules in a number of physiological processes. Excessive production of eicosanoids leads to several pathological conditions such as inflammation. In order to block the inflammatory effect of these compounds, upstream enzymes such as PLA₂ are valid targets. In the present contribution, molecular dynamic analysis was performed to evaluate the binding of diclofenac, 9-hydroxy aristolochic acid (9-HAA) and indomethacin to PLA₂. Obtained results revealed that 9-HAA could form a more stable complex with PLA₂ when compared to diclofenac and indomethacin. Furthermore, analysis of intermolecular binding energy components indicated that hydrophobic interactions were dominant in binding process. On the basis of obtained data, inhibitors bearing fused rings with hydrogen acceptor/donor substituent(s) interacted with His48 and Asp49 residues of the active site. More affinity toward PLA₂ might be envisaged through negatively charged moieties via interaction with Trp31, Lys34 and Lys69.