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.

B细胞淋巴瘤2（BCL-2）家族是细胞凋亡的主要调节因子之一。BCL-2家族的促凋亡和抗凋亡基因之间的复杂相互作用决定了细胞的凋亡平衡。BCL-2的抗凋亡成员的过表达指示细胞逃避死亡和癌症转移。在四个BCL-2同源域中，BH3域在抑制BCL-2表达中起关键作用。因此，目前正在研究模仿BH3的药物作为BCL-2抑制剂的适用性。在本研究中，我们遵循了基于结构的药效团建模方法，以识别BH3模拟小分子，从而制定出更精确和更有针对性的癌症治疗方案。为了鉴定具有相似结合特征的蛋白质，基于与Venetoclax（PDB-ID：6O0K）复合的Bcl-2的结构，生成了基于结构的药效团模型。从ZINC数据库中筛选出的具有良好适应性评分和药效团特征的化合物，经过（i）分子对接研究，（ii）分子力学通用的生化表面积（MM-GBSA）和（iii）吸收，分布，代谢，排泄和毒性（ADMET）预测。从分析中鉴定出两个分子：ZINC68728276和ZINC14166367，其对接得分分别为-7.323和-8.649 kcal / mol，自由结合能（MM-GBSA）分别为-72.913和-72.291 kcal / mol。这些复合物的结构参数和结合亲和力通过分子动力学模拟和分子力学-泊松-玻尔兹曼表面积（MM-PBSA）自由能计算得到验证，并与Venetoclax进行了比较。结果表明两种化合物的稳定性和良好的结合亲和力。研究确定ZINC68728276和ZINC14166367为可能具有计算机潜在Bcl-2抑制剂的作用，可以进一步考虑用于体外研究。