REPURPOSING NATURAL DRUGS AS DUAL-TARGET APOPTOSIS INDUCERS: AN IN SILICO APPROACH

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Dağ Ş. R., ALAGÖZ M. A.

Journal of Inonu University Vocational School of Health Services, cilt.14, sa.2, ss.380-391, 2026 (Scopus, TRDizin)

Özet

Some natural compounds are currently used as therapeutic agents in the treatment of various diseases. Beyond their established pharmacological effects, the potential repurposing of these natural drugs for new therapeutic targets, such as anticancer activity, remains an area of grow-ing scientific interest. The aim of this study was to investigate the repurposing potential of 4,787 small molecules, labelled as “natural drugs” in the ChEMBL database, against two key apoptotic regulators, Bcl-2 and caspase-3. A multi-step in silico workflow was applied, including molecular docking, MM-GBSA, and MD simulations. Molecular docking was performed with docking score thresholds of ≤ –8.0 kcal/mol for Bcl-2 and ≤ –6.0 kcal/mol for caspase-3. Thirty-seven compounds fulfilled both criteria, indicating potential dual modulatory activity. Further analysis of the candidates identified two promising compounds that emerged as the most effective. CHEMBL3545347 (Talfirastide) exhibited the strongest affinity for caspase-3 (–12.362 kcal/mol) and ranked fourth for Bcl-2 (–8.362 kcal/mol), whereas CHEMBL406291 (Bradykinin) achieved the highest Bcl-2 score (–9.545 kcal/mol) and ranked fifth for caspase-3 (–11.304 kcal/mol). MD simulations supported the molecular docking studies on talfirastide, further validating their binding stability and energetics, with average RMSD values of 3.0 Å and 2.4 Å for Bcl-2 and caspase-3, respectively. Collectively, these results indicate that talfirastide could function as a dual-target apoptosis modulator, simultaneously influencing pro-and anti-apoptotic mech-anisms. This dual-target binding profile highlights the potential of natural drugs as scaffolds for the development of next-generation apoptosis-targeting anticancer agents and provides a rational basis for future in vitro and in vivo studies.