Identification of Antagonists of Pro-Survival Bcl-2 from Morus alba in Human Malignancies

An In Silico Approach

Abstract

The target of most cancer chemotherapeutic agents is to drive cancer cells toward death, necessitating the need to find a fine balance between anti-apoptotic and pro-apoptotic proteins in maintaining cellular homeostasis. Any shift favoring the pro-apoptotic proteins is needed to drive cellular death in cancer chemotherapy. Therefore, this study uses molecular docking, ADMET predictions, and molecular dynamics simulations for the identification of potent inhibitors of anti-apoptotic Bcl-2 from Morus alba (mulberry). Our molecular docking study discovered that quercetin-3-(6- malonylglucoside) (-10.912kcal/mol) and epigallocatechin gallate (-9.750kcal/mol) recorded excellent binding affinity against human Bcl-2, better than popular standard drugs, venetoclax (-9.468(kcal/mol) and navitoclax (-9.058kcal/mol). Interactions profile summary clearly showed that hydrophobic interactions at TRP141, VAL145, and TYR105 were consistently maintained by the ligands, and all the compounds, except venetoclax, consistently maintained the hydrogen bonding at TYR105. MD simulation analysis showed that the protein and ligand RMSD for the quercetin-3-(6-malonylglucoside)-Bcl-2 complex fell within permissible range, suggesting the ligand is capable of functioning as apposite antagonists of Bcl-2. Epigallocatechin gallate also bind excellently with the target, and both ligands showed favorable ADMET parameters. Summarily, this study identifies two compounds of mulberry as potential drug candidate in the management of known human malignancies, and therefore suggest the compounds should further be assessed through in vitro and in vivo approaches to validate the reports documented here.