Abstract
The search for mechanism-based anti-inflammatory therapies is of fundamental importance to avoid undesired off-target effects. Phospholipase A(2) (PLA(2)) activity is a potential molecular target for anti-inflammatory drugs because it fuels arachidonic acid needed to synthesize inflammation mediators, such as prostaglandins. Herein, we aim to investigate the molecular mechanism by which β-keto amyrin isolated from a methanolic extract of Cryptostegia grandiflora R. Br. Leaves can inhibit inflammation caused by Daboia russellii viper (DR) venom that mainly contains PLA(2). We found that β-keto amyrin neutralizes DR venom-induced paw-edema in a mouse model. Molecular docking of PLA(2) with β-keto amyrin complex resulted in a higher binding energy score of -8.86 kcal/mol and an inhibition constant of 611.7 nM. Diclofenac had a binding energy of -7.04 kcal/mol and an IC50 value of 620 nM, which predicts a poorer binding interaction than β-keto amyrin. The higher conformational stability of β-keto amyrin interaction compared to diclofenac is confirmed by molecular dynamics simulation. β-keto amyrin isolated from C. grandiflora inhibits the PLA(2) activity contained in Daboia russellii viper venom. The anti-inflammatory property of β-keto amyrin is due to its direct binding into the active site of PLA(2), thus inhibiting its enzyme activity.