Identification of Compounds Against Anti-apoptotic Bcl-2 Protein Using Docking Studies

The high expression of anti-apoptotic Bcl-2 protein in cancer cells can confer resistance to apoptosis, allowing cells to evade cell death signals and continue proliferating. Therefore, Bcl-2 has become a crucial target for cancer therapy. In this work, we looked for new drugs targeting Bcl-2 that can induce apoptosis in cancer cells and improve treatment effectiveness like chemotherapy. In silico approaches, such as molecular docking, were used to identify potential new drugs by screening the Enamine collection (HLL-460) against two conformations of the Bcl-2 protein obtained by molecular dynamics (MD) simulations. Molecular docking was focused on two specific sites of Bcl-2; the binding groove and the flexible loop domain (FLD), which play an essential role in regulating the apoptotic process. Compounds with docking scores less than those of the reference drugs (Venetoclax and Taxol) were selected. They were analyzed by PASS online, which predicted putative anti-cancer properties for ten compounds; of these, three candidates targeted binding groove, five to FLD, and two can bind to both sites; these compounds were selected and analyzed. The drug-like properties of the ten compounds passed Lipinski's rules, their pharmacokinetic profiles were excellent, safe, and had potential anti-neoplastic activity. Overexpression of anti-apoptotic proteins leads to resistance to apoptosis in cancer cells. BH3 mimetic drugs function by blocking these proteins and promoting apoptosis. Screening using molecular docking was performed to search for new BH3 mimetic drugs, generating the identification of ten compounds that attach to the binding groove, or FLD, in the Bcl-2 protein with excellent theoretical pharmacokinetic profiles.image