Integrated In-Silico Approach to Elucidate the Anticholestatic Potential of Garcinia indica Choisy Against Clavulanic AcidInduced cholestasis

Abstract

indica represents a structurally rational, multi-target natural product candidate for the pharmacological management of drug-induced cholestasis Abstract Background and Purpose: Drug-induced cholestasis (DIC), a clinically significant subtype of drug-induced liver injury (DILI), is characterized by impaired bile acid homeostasis, oxidative stress, and progressive hepatocellular damage. Clavulanic acid (CLAV), the primary hepatotoxic component of amoxicillin-clavulanate (AC), disrupts farnesoid X receptor (FXR) and NRF2 signalling while regulatory pathway, leading to impaired BSEP-mediated bile acid transport, activation of inflammatory signalling, and altered cholesterol metabolism through HMGCR dysregulation. Current therapeutic options remain limited in efficacy, creating a need for safer and more effective multi-target approaches. Garcinia indica Choisy, a medicinal plant rich in flavonoids and polyisoprenylated benzophenones, was investigated for its potential anticholestatic activity. Experimental Approach: 69 phytoconstituents of G. indica were screened using ADMET profiling. Network pharmacology analysis was performed to identify overlapping targets associated with clavulanic acid-induced cholestasis. Four key proteins involved in disease progression FXR, BSEP, TNF-α, and HMGCR-were selected for molecular docking studies, followed by 100 ns molecular dynamics simulation to assess complex stability. Key Results: 24 compounds satisfied the drug-likeness and safety criteria. The identified 101 overlapping targets enriched the pathways related to bile secretion, ABC transporters, cholesterol metabolism, NF-kB signalling, and PI3K-Akt signalling. Docking analysis demonstrated strong binding affinities of apigenin toward FXR (-9.1 kcal/mol), isoxanthochymol toward TNF-α (-10.0 kcal/mol), quercetin toward BSEP (-8.3 kcal/mol), and morelloflavone toward HMGCR (-8.3 kcal/mol). Molecular dynamics simulation further supported the stability of the lead ligand-protein complexes throughout the simulation period. Conclusion and Implications: The study suggests that G. indica phytoconstituents, like apigenin and morelloflavone, may have promising multi-target potential against cholestasis caused by clavulanic acid and further, need to be validated through experimental investigations.