<i>In silico</i> approach to screen anti-inflammatory phytochemicals: targeting cytosolic phospholipase A ₂ 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.