β-keto amyrin isolated from Cryptostegia grandiflora R. br. inhibits inflammation caused by Daboia russellii viper venom: Direct binding of β-keto amyrin to phospholipase A2

The search for mechanism-based anti-inflammatory therapies is of fundamental importance to avoid undesired off-target effects. Phospholipase A2 (PLA2) 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 PLA2. We found that β-keto amyrin neutralizes DR venom-induced paw-edema in a mouse model. Molecular docking of PLA2 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 PLA2 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 PLA2, thus inhibiting its enzyme activity. [Display omitted] •A methanolic extract of G. grandiflora contains β-keto amyrin.•β-keto amyrin inhibits inflammation caused by Daboia russellii viper venom.•The stability of β-keto amyrin-PLA2 complex is higher than diclofenac-PLA2 complex.•β-keto amyrin binds into the active site of PLA2.