Antiapoptotic proteins as targets for bioactive compounds: structural parameters and molecular design

Plant polyphenolics showcase multiple cancer activities, from antioxidant and anti-inflammatory to cytotoxic in different cancer models. Most cancers arise due to the over expression of antiapoptotic protein Bcl-2, which hinders the programmed cell death and lead to uncontrolled cell differentiation. The BH3 domain in Bcl-2 plays a crucial role in suppressing Bcl-2 expression, making BH3 mimetics essential in cancer treatments by promoting apoptosis in malignant cells. However, mutations in the BH3 domain have been discovered to cause resistance to currently available BH3 mimetics. Hence, numerous efforts are underway to develop BH3 mimetics as potential Bcl-2 inhibitors. This work investigates the binding interactions of five potential bioactive compounds with wild type (WT) Bcl-2 and mutant Bcl-2G101V protein, with the aim of elucidating their BH3 mimetic activity. The compounds were subjected to rigid and flexible receptor docking. Venetoclax was employed as the control ligand and literature available BH3 mimetics were docked into these target proteins to find common binding motifs of BH3 mimetics. The docking calculations were resulted procyanidin B2 with good docking scores, -8.30 and -8.80 kcal/mol with Bcl-2WT and Bcl-2G101V, respectively. This suggests its potential as a Bcl-2 inhibitor, warranting further consideration for in-depth investigation.