B-Cell lymphoma 2 (BCL-2) regulates cell death in humans. In this study, combined multiscale in silico approaches and in vitro studies were employed. A small-molecule library that includes more than 210 000 compounds was used. The predicted therapeutic activity value (TAV) of the compounds in this library was computed with the binary cancer quantitative structure-activity relationships (QSAR) model. The molecules with a high calculated TAV were used in 26 individual toxicity QSAR models. As a result of this screening protocol, 288 nontoxic molecules with high predicted TAV were identified. These selected hits were then screened against the BCL-2 target protein using hybrid docking and molecular dynamics (MD) simulations. The interaction energies of identified compounds were compared with two known BCL-2 inhibitors. Then, the short MD simulations were carried out by initiating the best docking poses of 288 molecules. Average MM/GBSA energies were computed, and long MD simulations were employed to selected hits. The same calculations were also applied for two known BCL-2 inhibitors. Moreover, a five-site (AHRRR) structure-based pharmacophore model was constructed, and this model was used in the screening of the same database. On the basis of hybrid data-driven ligand identification study, final hits were selected and used in in vitro studies. Based on results of the time-resolved fluorescence resonance energy transfer (TR-FRET) analysis, further filtration was carried out for the U87-MG cell line tests. MTT cell proliferation assay analysis results showed that selected three potent compounds were significantly effective on glioma cells.
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