Network pharmacology and in-silico approaches to elucidate the antimicrobial mechanism of Aesculus assamica Griff. for the treatment of skin infection

Abstract

ABSTRACT The genus Aesculus, recognized for its therapeutic applications in traditional medicine, includes Aesculus assamica Griff. (AA), an underexplored species native to the eastern Himalayas. Traditionally, AA has been used for its anti-inflammatory, antifungal, and cytotoxic properties. Its stem and bark are also used for fish poisoning, likely due to the presence of saponins and rotenones. Despite its ethnomedicinal relevance, AA remains poorly studied with limited scientific documentation. This study investigates the therapeutic potential of AA in treating bacterial skin infections—a growing public health concern in India. An integrative in silico approach was employed, incorporating network pharmacology, molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling, DFT (Density Functional Theory) calculations, and antibacterial activity prediction using antiBac-Pred to identify potential anti-infective leads from AA. Network pharmacology analysis identified nine overlapping targets associated with skin infections, with STAT3, mTOR, PTGS2, and TLR4 emerging as central nodes in the protein–protein interaction network. KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) enrichment analyses suggested a key role for the HIF-1 signaling pathway, particularly through STAT3 and mTOR. Molecular docking revealed strong binding affinities of compounds assamicin-I & II (ASS-I and ASS-II) toward STAT3 (−46.7 and −47.2 kcal/mol), while 1-hentriacontanol (1-HTC) showed high affinity for mTOR (−63.04 kcal/mol), indicating potential to modulate host immune responses. DFT calculations confirmed the electronic stability and reactivity of 1-HTC and the triterpenoid compounds. ADMET analysis demonstrated favorable pharmacokinetic profiles for most triterpenoids and long-chain alcohols. Notably, 1-HTC, β -sitosterol ( β -s), and oleanolic acid (OA) exhibited good oral bioavailability and drug-likeness, whereas ASS-I and ASS-II, despite minor rule violations, appear suitable for topical or non-oral applications. Most phytoconstituents also showed low metabolic liability and minimal central nervous system penetration, supporting their potential use in treating peripheral infections such as skin diseases. Among the compounds, 1-HTC emerged as the most promising lead for broad-spectrum and anaerobic bacterial inhibition, with stearic acid identified as a backup candidate. Additionally, theasapogenol B (T-B) and oleanolic acid (OA) may be valuable in selective or combination therapies targeting pathogens like Staphylococcus lugdunensis.

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