In Silico Study of Non-Volatile Compounds from Citrus aurantiifolia Peels Targeting MMP-9 and TNF-α in Chronic Wound Management

Abstract

Chronic wounds represent a major clinical problem characterized by persistent inflammation and excessive degradation of the extracellular matrix mediated by TNF-α and MMP-9. The aim of this study was to identify non-volatile compounds from Citrus aurantiifolia (lime) peel as potential inhibitors of these two therapeutic targets for topical application. Phytochemicals were filtered in silico according to physicochemical “minimum requirements” for skin penetration (MW <500 Da, Log P 1–5) and safety profiles (AMES toxicity and skin reaction). Molecular docking against MMP-9 and TNF-α, followed by 50 ns molecular dynamics (MD) simulations, was performed to evaluate binding interactions and complex stability. 3′-Hydroxygenkwanin (−10.1 kcal/mol) and luteolin (−10.0 kcal/mol) exhibited particularly favorable predicted binding affinities for MMP-9, whereas obacunone and limonin showed more favorable dual-target binding profiles (−9.1 to −10.3 kcal/mol) than doxycycline (−7.6 kcal/mol for MMP-9 and −8.0 kcal/mol for TNF-α). Docking analysis showed interactions with important residues, including His226 in MMP-9 and Tyr119 in TNF-α. The structural stability of the 3′-hydroxygenkwanin and luteolin complexes with MMP-9, as well as the obacunone, luteolin, and limonin complexes with TNF-α, was supported by MD simulations. In conclusion, 3′-hydroxygenkwanin represents a promising MMP-9-targeting candidate, while obacunone and limonin show particularly promising dual-target binding profiles. These findings support selected C. aurantiifolia phytochemicals as potential lead candidates for further investigation in topical chronic wound management.