Anti-inflammatory potential of Grewialin from Grewia optiva: insights from molecular docking, ADMET, DFT, and in-vitro studies

Abstract

Grewia optiva, a medicinal plant native to northern Pakistan, has traditionally been valued for managing pain and inflammation. Among its bioactive constituents, Grewialin, a compound isolated from the stem bark, has garnered attention as a promising candidate for anti-inflammatory drug development. This study aimed to evaluate the anti-inflammatory potential of Grewialin using a combination of in-silico and in-vitro approaches, focusing on its effects on lipoxygenase (LOX) and neutrophil respiratory burst activity. Furthermore, the pharmacological and toxicological profiles of Grewialin were assessed to support its potential as a lead compound. Structure-based virtual screening identified Grewialin as a potential LOX inhibitor. Molecular docking studies revealed a significant binding score of -6.874 kcal/mol, indicating strong interactions with the active site of the LOX enzyme (5-LOX). ADMET profiling demonstrated its favourable pharmacokinetic and toxicological properties, while density functional theory (DFT) calculations highlighted its balanced electrophilic and nucleophilic properties, reflecting its chemical stability and reactivity. Experimental validation through in vitro assays confirmed Grewialin's potent inhibitory activity against LOX, with an IC50 value of 31.9 ± 0.03 µM. Additionally, Grewialin effectively inhibited neutrophil respiratory burst activity, achieving an IC50 of 317.62 ± 0.059 µM, further supporting its anti-inflammatory potential. These findings position Grewialin as a multifaceted anti-inflammatory agent with dual action targeting LOX and neutrophil respiratory burst activity. The combined in-silico and in-vitro results underscore its potential as a lead compound for developing anti-inflammatory drugs. Further research is warranted to explore its therapeutic mechanisms and optimize its efficacy, bridging traditional medicinal knowledge with modern pharmacological advancements. It is worth mentioning, though, that, in line with the aforementioned dual inhibitory profiles, Grewialin also demonstrated moderate potency (LOX and neutrophil respiratory), thus indicating that additional structural optimization or adequate formulation design is necessary to progress it toward therapeutic development. By leveraging the unique properties of Grewialin, this study contributes to the ongoing pursuit of novel, natural compounds for the effective management of inflammatory diseases. This comprehensive evaluation highlights the significance of Grewia optiva as a source of bioactive compounds, emphasizing the need for further exploration into its pharmacological application.

Keywords: Grewia optiva; Grewialin; ADMET; And DFT; Anti-inflammatory; Bioactivity; Docking; Drug development; LOX inhibitor.