Revealing the rationale behind the differential neutralization of phospholipase A2 (PLA2) enzymes in snake and bee venom by varespladib (LY-315920), a small molecule PLA2 inhibitor
Abstract
Abstract Phospholipase A2 (PLA2) enzyme found in snakes, bees, and wasps’ venoms is responsible for toxicity and pathophysiology of envenomation. Varespladib (VP, LY-315920) is among the extensively researched small molecule inhibitors targeting snake venom (SV) PLA2 and PLA2-like proteins. Interestingly, it could not neutralize bee venom (BV) PLA2. To reveal this puzzle, we compared VP’s in silico binding mechanisms with PLA2s from India’s ‘Big Four’ snake venoms (BFSVs, Naja naja, Daboia russelii, Echis carinatus, and Bungarus caeruleus), nine viper venoms from four continents, and BV. VP binds SV-PLA2s in the same position but in a different position in the BV-PLA2s due to a clash between its phenyl ring and residues Tyr89 and Ile91, which might be the reason behind its universal activity against SV-PLA2s but negligible activity against BV-PLA2. Molecular docking and dynamics simulations identified optimal VP binding conformations with BFSV and BV-PLA2 proteins. In silico analysis results showed that the BFSV-PLA2–VP complex exhibited significantly greater binding affinity and stability than other PLA2–VP complexes, suggesting enhanced molecular interactions. The spectrofluorometric binding data showed a significantly higher binding affinity of VP with BFSV-PLA2s than BV-PLA2s, corroborated by differential inhibition of catalytic activity and anticoagulant activity of PLA2 enzymes from BV and SVs. VP showed significant neutralization of in vivo toxicity, generating…
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