Molecular dynamic simulations on an inhibitor of anti-apoptotic Bcl-2 proteins for insights into its interaction mechanism for anti-cancer activity

Abstract

Inhibition of normal cellular apoptosis or programed cell death is the hallmark of all cancers. Apoptotic dysregulation can result in numerous pathological conditions, such as cancers, autoimmune disorders, and neurodegeneration. Members of the BCL-2 family of proteins regulate the process of apoptosis by its promotion or inhibition and overexpression of the pro-survival anti-apoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1) has been associated with tumor maintenance, growth and progression Small molecules and peptides which bind the BH3 binding groove of these proteins have been explored in the recent times for their anticancer potential. The first anticancer agents targeting this family of proteins were aimed primarily toward inhibition of Bcl-2. An elevated level of Mcl-1, despite Bcl-2 inhibition, continues to be a cause for resistance in most cancers. However, in silico exploration of Mcl-1 specific drugs and their associated mechanisms have not been clearly elucidated. In order to understand the same, we have carried out docking and molecular dynamic simulations on ABT-263 (Navitoclax), an orally active inhibitor of Bcl-2, Bcl-xL, and Bcl-w proteins; Obatoclax, a pan-Bcl-2 inhibitor as well as Maritoclax, an Mcl-1 specific inhibitor. Docking studies revealed that binding to the hydrophobic grooves is a prerequisite for action on the BCL protein and the binding mechanism and chemical space utilization dictates stability as well as specificity of the inhibitor molecular dynamic simulations showed that on binding, the α-helices of these proteins exhibited less fluctuations than loop regions, also hydrophobic contacts and hydrogen bonding were observed to be the predominant interactions in the drug-receptor complexes.

Communicated by Ramaswamy H. Sarma

Graphical Abstract

Keywords:

• Apoptosis
• Bcl-2 inhibitors
• docking
• molecular dynamics
• pan-Bcl-2 inhibitors

Acknowledgments

The authors would like to thank UGC-SAP, New Delhi, India, for the Research Fellowship.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by UGC-SAP, New Delhi, India. The molecular modeling was carried out in CADD facility funded by TEQIP grant and by UGC-CAS for software upgradation.