Steroids from Talaromyces stipitatus as potential hepatocellular carcinoma inhibitors: A computational study

Hepatocellular carcinoma frequently exhibits evasion of apoptosis, rendering the anti-apoptotic Bcl-2 protein a pertinent therapeutic target. Steroids from Talaromyces stipitatus were evaluated as Bcl-2 inhibitors using molecular docking, molecular dynamics simulation, MMGBSA free-energy estimation, ADMET prediction, and DFT descriptors. Docking prioritized CPD2 over Paclitaxel. It also indicated accommodation within a conserved pocket supported by hydrogen-bond and hydrophobic interactions. Molecular dynamics suggested sustained stability and compactness for the CPD2-Bcl-2 complex. In contrast, the reference complex exhibited comparatively larger conformational excursions. MMGBSA favored CPD2, with improved net association attributable primarily to a reduced solvation penalty. ADMET profiling indicated limited aqueous solubility and a shared hERG II liability, while predicting no hepatotoxicity alert for CPD2. DFT descriptors were consistent with higher electronic responsiveness for CPD2 relative to the reference. These findings suggest that CPD2 may serve as a promising scaffold for developing Bcl-2-targeted therapeutic strategies against HCC. Future in vitro and in vivo studies are required to validate these computational predictions and guide lead optimization.