Crystal structure of phospholipase A₂ in complex with 1-naphthaleneacetic acid

Phospholipase A₂ (PLA₂ ) is one of the rate limiting enzymes involved in the production of arachidonic acid, a potent inflammatory mediator. PLA₂ is widely distributed all over the animal kingdom. It is also seen in inflammatory exudation and venoms of different organisms. The studies demonstrated that PLA₂ inhibitors have broad spectrum activities that they can either be used against inflammation or envenomation. In this study, the inhibitory activity of 1-napthaleneacetic acid (NAA) against porcine pancreatic PLA₂ has been explained through isothermal titration calorimetry and enzyme kinetics studies. The atomic level of interactions of NAA with PLA₂ was also studied using X-ray crystallography. Apart from these findings, the theoretical binding affinities and mode of interactions of two naphthalene-based NSAIDs such as naproxen (NAP) and nabumetone (NAB) were studied through molecular modeling. The studies proved that the selected ligands are binding at the doorway of the active site cleft and hindering the substrate entry to the active site. The study brings out a potential scaffold for the designing of broad spectrum PLA₂ inhibitors which can be used for inflammation or envenomation. © 2018 IUBMB Life, 70(10):995-1001, 2018.