Structure-based design approach of potential BCL-2 inhibitors for cancer chemotherapy.

B-cell lymphoma 2 (BCL-2) family is one of the chief regulators of cellular apoptosis. The intricate interactions between pro-apoptotic and anti-apoptotic genes of the BCL-2 family dictate the apoptotic balance of the cell. An overexpression of the anti-apoptotic members of BCL-2 is indicative of cell death evasion and cancer metastasis. Among the four BCL-2 homology domains, the BH3 domain plays a key role in the suppression of BCL-2 expression. Therefore, BH3-mimetic drugs are currently investigated for their suitability as BCL-2 inhibitors. In the present study, we followed a structure-based pharmacophore modelling approach to identify BH3-mimetic small molecules, to formulate a more precise and targeted cancer treatment regimen. To identify proteins with similar binding features, a structure-based pharmacophore model was generated based on the structure of Bcl-2 complexed with Venetoclax (PDB-ID:6O0K). Compounds with good fitness score and pharmacophore features, screened from the ZINC database, were subjected to (i) molecular docking studies, (ii) molecular mechanics-generalized Born surface area (MM-GBSA), and (iii) absorption, distribution, metabolism, excretion and toxicity (ADMET) prediction. From the analysis, two molecules were identified: ZINC68728276 and ZINC14166367, with docking scores of -7.323 and -8.649 kcal/mol and free binding energies (MM-GBSA) of -72.913 and -72.291 kcal/mol, respectively. The structural parameters and binding affinity of these complexes were validated through molecular dynamics simulation and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) free energy calculations and compared with Venetoclax. The results indicated stability and good binding affinity of both the compounds. The study identified ZINC68728276 and ZINC14166367 as in silico potential Bcl-2 inhibitors, which can be further considered for in vitro studies.