Molecular modeling of the inhibition of enzyme PLA₂ from snake venom by dipyrone and 1‐phenyl‐3‐methyl‐5‐pyrazolone

Abstract

Abstract Phospholipases A 2 (PLA 2 ) are enzymes that trigger the degradation cascade of the arachidonic acid, leading to the formation of pro‐inflammatory eicosanoids. The selective inhibition of PLA 2 s is crucial in the search for a more efficient anti‐inflammatory drug with fewer side effects than the drugs currently used. Hence, we studied the influences caused by two pyrazolonic inhibitors: dipyrone (DIP) and 1‐phenyl‐3‐methyl‐5‐pyrazolone (PMP) on the kinetic behavior of PLA 2 from Crotalus adamanteus venom. Molecular modeling results, by DFT and MM approaches, showed that DIP is strongly associated to the active site of PLA 2 through three hydrogen bonds, whereas PMP is associated to the enzyme just through hydrophobic interactions. In addition, only PMP presents an intramolecular hydrogen bond that make difficult the formation of more efficient interactions with PLA 2 . These results help in the understanding of the experimental observations. Experimentally, the results showed that PLA 2 from C. adamanteus present a typical Michaelian behavior. In addition, the calculated kinetic parameters showed that, in the presence of DIP or PMP, the maximum enzymatic velocity ( V MAX ) value was kept constant, whereas the Michaelis constant ( K M ) values increased and the inhibition constant ( K I ) decreased, indicating competitive inhibition. These results show that the phenyl‐pyrazolonic structures might help in the development and design of new drugs able to selectively inhibit PLA 2 . © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008