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

K. H. Santhosh, V. Krishna, K. Kemparaju, H. Manjunatha, R. Shashi Kumar, A. Mukherjee, S. E. Gomez Mejiba, D. C. Ramirez, B. S. Ravindranath

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number107679
JournalToxicon
Volume241
DOIs
Publication statusPublished - 04-2024

All Science Journal Classification (ASJC) codes

  • Toxicology

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