In Silico Investigation of DLBS3233 Bioactives Targeting Inflammatory, Metabolic, and Cholesterol Transport Pathways in Gallstone (Cholelithiasis) Pathogenesis

Resumen

Abstract
Background: Gallstone disease remains a prevalent hepatobiliary disorder with rising incidence globally and limited pharmacologic options [1-2]. Ursodeoxycholic acid (UDCA), the main therapy, is restricted to small non-calcified stones, requires prolonged administration, and has a high recurrence rate [3]. DLBS3233 an Indonesian bioactive fraction derived from Lagerstroemia speciosa and Cinnamomum burmannii is known for its metabolic benefits through PPARγ modulation, suggesting potential therapeutic relevance in cholesterol-related diseases such as gallstone formation [4].This study evaluates the molecular interaction of DLBS3233 bioactives with key targets in the pathogenesis of gallstone disease [5-6].
Methods: An in silico ligand–protein docking approach was performed using CB-Dock2 to assess the interactions of two major DLBS3233 bioactive compounds, Cinnamtannin B1 (C1) and Ellagic acid (C2), with ten receptor proteins involved in cholesterol transport (ABCG5/8, NPC1L1), metabolism (CYP7A1, HMG-CoA reductase), nuclear regulation (FXR, LXRα, PPARγ), inflammation (IL-6, TNF-α), and vascularization (VEGFR-2). Bioactivity prediction (Pa), toxicity classification, and drug-likeness evaluation (Lipinski, Pfizer, GSK filters) were performed using WAY2DRUG, Protox II, and ADMETLab.
Results: C1 demonstrated the strongest overall binding affinity (–101.8 kcal/mol), exceeding UDCA, statins, fibrates, metformin, and pioglitazone. C1 showed high affinity toward CYP7A1, HMG-CoA reductase, IL-6, TNF-α, PPARγ, and VEGFR-2, suggesting potent metabolic, anti-inflammatory, and vascular-modulatory effects. C2 exhibited moderate yet consistent binding strength (–82.7 kcal/mol) but demonstrated superior drug-likeness and lower toxicity (LD₅₀ 2991 mg/kg; class 4). Both compounds showed favorable Pa scores (>0.4), indicating predictive bioactivity across key metabolic and inflammatory pathways.
Conclusion: DLBS3233 bioactives possess strong multi-target interactions relevant to gallstone pathogenesis, surpassing several existing therapeutic agents in silico. C1 offers potent effects, while C2 provides safety and pharmacokinetic advantages, together supporting the potential of DLBS3233 as an adjunct therapy alongside UDCA. Further in vitro, in vivo, and clinical studies are warranted to validate these findings.

Keywords : gallstone, cholelithiasis, phytochemicals, natural products