In silico approach to screen anti-inflammatory phytochemicals: targeting cytosolic phospholipase A2 and phospholipase C

Phospholipase A2 (PLA2) have various inflammatory responses by catalysing the release of arachidonic acid and lysophospholipids from membrane phospholipids. Amongst PLA2 variants, cytosolic PLA2 (cPLA2) is central to inflammation, while phospholipase C (PLC) is involved in macrophage-mediated inflammation, significant in various infectious diseases and cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to prevent inflammation by inhibiting COX 1 and COX 2 enzymes but have several side effects. They affect the gastric mucosa wall, causing stomach and duodenal ulcers. This necessitates desirable alternative enzymes inhibitor with less side effects. In the present study, 57 phytochemicals possessing PLA2 inhibiting properties were screened and compared with chemically synthesised Varespladib. Based on pharmacological activity as analysed from Way2Drugs server, p-Coumaric acid suited best phytochemical against PLA2 and PLC. Molecular docking using HADDOCK server for p-Coumaric acid and reference compound Varespladib exhibited binding score of −51.3 ± 1.4 and −32.3 ± 1.5 with PLA2 respectively whereas displayed binding score of −55.6 ± 3.2 and −31.4 ± 1.3 respectively with PLC. Further, the fact was validated by a comparative 250 ns molecular dynamics (MD) simulation using the Desmond package and MM-GBSA experiments were carried out to analyse the thermodynamic nature of receptor-ligand complex. The MD simulation showed that the phytochemical p-Coumaric acid exhibited strong interactions with cPLA2 and interacted moderately with PLC during the simulation. However, the reference molecule Varespladib was observed to be interacted strongly with cPLA2 and feebly with the PLC. This is the first report on the strong efficacy of p-Coumaric acid against cPLA2.