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

SANTHOSH, K.H.; KRISHNA, V.; KEMPARAJU, K.; MANJUNATHA, H.; SHASHI KUMAR, R.; MUKHERJEE, A.; GOMEZ MEJIBA, S.E.; RAMIREZ, D.C.; RAVINDRANATH, B.S.

TOXICON

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2024 vol. 241

0041-0101

AbstractThe 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.Graphical abstractImage 1Download : Download high-res image (190KB)Download : Download full-size image