Ligand-based design approach of potential Bcl-2 inhibitors for cancer chemotherapy

Background and Objectives: Overexpression of prosurvival Bcl-2 family members make tumor cells resistant to conventional cancer therapeutic agents. It is commonly observed feature in many different types of human tumors. Hence, small-molecules as Bcl-2 inhibitors may have a promising therapeutic potential for the treatment of human cancer. The given study focusses on development of novel and small Bcl-2 inhibitors using ligand-based drug design approach. Methods: Ligand based pharmacophore was generated using the PHASE tool of Schrodinger and screened ZINC database through ZINCPharmer webserver to identify compounds with similar features. Compounds having good fitness score were selected for molecular docking and binding interactions were compared with drugs in market as well as trials. QSAR model was generated using advanced AutoQSAR tool and validated for prediction of unknown compounds. QSAR prediction of in silico active identified three potential compounds and were subjected to investigate stability by molecular dynamics simulations and MM-PBSA binding energy calculations. Results: Study identified three in silico potential molecules with good stability and binding affinity. Further substructure search and pIC(50) value prediction has identified six more molecules. Total nine molecules have demonstrated good drug likeness features. Conclusion: Final oral rat LD50 calculation of nine molecules has identified three hit molecules i.e., ZINC76760927, ZINC76768675 and ZINC52767796 for further in vitro and in vivo testing as safe and potential Bcl-2 inhibitors. (C) 2021 Elsevier B.V. All rights reserved.