Virtual Screening of Representative Natural Products Library for TGF-β-Mediated Liver Cirrhosis: An in silico and in vitro Multi-Target Study

Haytham Mohamed Makki, Ki-Hoon Park, Youngbuhm Huh, Ja-Eun Kim, Ji Lee, Hwajin Lee, Sunyoung Kim, Hiroyuki Konishi, Na Jeong, Junyang Jung and Hyung-Joo Chung

Background and Objective: Transforming Growth Factor Beta (TGF-β) significantly contributes to liver cirrhosis pathogenesis by promoting hepatic fibrosis. Drug discovery using molecular docking (MD) offers valuable insights into potential therapeutic candidates. This study investigated the early-stage discovery of potential natural drug candidates targeting the non-canonical TGF-β signaling pathway in liver cirrhosis pathogenesis. Materials and Methods: A virtual screening of the Korea Chemical Bank (KCB) natural compounds library was performed against key proteins, including TGF-β Receptor Type-1 (TGF-βR1), Focal Adhesion Kinase (FAK) and Phosphoinositide 3-Kinase (PI3K), using MD. Bioinformatics analysis identified additional targets such as Matrix Metallopeptidase 13 (MMP13) and explored pathway enrichments. The predicted Absorption, Distribution, Metabolism and Excretion (ADME) properties of promising compounds were evaluated. Experimental validation on HepG2 cells using RT-qPCR was conducted for the selected compounds. Results: TGF-βR1 binders from the KCB library exhibited higher binding affinities (-11.2 to -10.4 kcal/mol) than the reference inhibitor galunisertib (-10.0 kcal/mol). Bioinformatics identified MMP13 as a potential target for alcoholic liver cirrhosis, with enriched pathways related to cancer, p53 and PI3K-Akt signaling. Notably, dihydrosanguinarine (DHS) and eriocitrin showed promising inhibitory interactions with fibrogenic kinases. The ADMET analysis indicated DHS, trisindoline and α-Naphthoflavone (α-NF) as viable oral candidates. The RT-qPCR results highlighted luteolin’s inhibitory effects, whereas diosmetin and α-NF upregulated target gene expressions. Conclusion: In silico findings underscore the potential of promising natural compounds for liver cirrhosis therapy. However, further in vitro and in vivo studies are needed to confirm their antifibrotic efficacy and therapeutic value.

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