Structure-Based Identification of Natural Product-Derived BCL-2 Inhibitors as Potential Therapeutics for...

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, remains a major therapeutic challenge due to its poor prognosis and resistance to conventional therapies. In this study, we employed a structure- based virtual screening strategy to identify novel small-molecule inhibitors derived from natural products targeting the anti-apoptotic protein BCL2, a key driver of HCC progression.

A curated library of 600 phytochemicals was docked against the BCL2 protein model using molecular docking, followed by ADMET profiling and Molecular Dynamics (MD) simulations.

Among the screened compounds, three candidates (Azadirone, Hydroxyethylamine scaffold, and Pyridine-3-carboxylic acid) demonstrated strong binding affinity and stable interaction patterns with critical residues such as GLN429 and TRP601. in silico ADMET analysis indicated favorable safety profiles, with no predicted carcinogenicity or toxicity, though oral bioavailability limitations were noted. MD simulations confirmed structural stability and strong protein ligand binding, with Hydroxyethylamine showing the most consistent conformational performance.

The identified compounds showed potential interactions with the BCL2 target, suggesting the potential of phytochemical-derived molecules as apoptosis-modulating agents in HCC. This combination of docking, ADMET, and MD simulations provided a comprehensive computational evaluation, consistent with the existing trends in natural product-based and AI-aided drug discovery strategies.

This study presents three lead candidates in natural sources that are likely to be used as BCL2 inhibitors in the treatment of HCC. The integrative computational approach offers an excellent platform for the discovery of apoptosis-targeting therapeutics, hastening their development and facilitating further experimental validation.