Homology Modeling and Docking Studies of Bcl-2 and Bcl-xL with Small Molecule Inhibitors: Identification and Functional Studies

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Author(s): Abdul Ajees Abdul Salam*, Upendra Nayek, Dhanya Sunil*.

Journal Name: Current Topics in Medicinal Chemistry

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Apoptosis is a vital physiological process, which is observed in various biological events. The anti-apoptotic and pro-apoptotic members of Bcl-2 family are the most characterized proteins which are involved in the regulation of apoptotic cell death. The anti-apoptotic proteins such as Bcl-2 and Bcl-xL prevent apoptosis, whereas pro-apoptotic members like Bax and Bak, elicit the release of caspases from death antagonists inducing apoptosis. Thus, the Bcl-2 family of proteins play a vital role in controlling programmed cell death. Over expression of anti-apoptotic Bcl-2 proteins are often directly associated with various kinds of cancer. Developing suitable inhibitors for controlling the elevated levels of these proteins got much attention in last decade. As of now, protein data bank has more than 400 structures of Bcl-2 family proteins, both ligand freeand co-crystallized with several inhibitors. Apart from the x-ray crystallography and NMR studies, homology modelling and docking studies also play a significant role in identifying the key inhibitors for these proteins. The authors have developed and tested successfully, several series of indolepharmacore containing inhibitors for Bcl-2, and Bcl-xL proteins based on the homology modelling, docking and suitable biochemical and apoptosis assays. This review summarizes the molecular interactions of Bcl-2 and Bcl-xL proteins with the ligands available at the Protein Data Bank as of now. Based on this study, the key residues of Bcl-2, Bcl-xl proteins interacting with potential drug molecules are identified. The present appraisal also focuses on the role of computational algorithms in developing potential drug molecules,with more emphasis on the role of homology modelling and docking studies in developing inhibitors for Bcl-2, and Bcl-xL proteins in cancer therapy.

Keywords: Apoptosis, Bcl-2, Bcl-xL, Docking, Homology modelling, Indole derivatives, Protein Data Bank.

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(E-pub Ahead of Print)
DOI: 10.2174/1568026619666190119144819
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