Designing of de novo dual inhibitors for Bcl-XL and Mcl-1 of Bcl2-family proteins by computational methods

Anti-apoptotic proteins such as Bcl-XL and Mcl-1 have been reported to be over expressed in most cancer forms and consequently, designing dual inhibitors to the proteins is becoming an important strategy in cancer chemotherapy. Interestingly, the Bcl-XL and Mcl-1 show differential binding affinities with BH3-only peptides of Bim and NOXA, notwithstanding their similar three-dimensional folds. The structural determinants for the differential interactions of the proteins with the BH3-only peptides have been scrutinized using molecular docking and temperature-dependent dynamic studies. The comprehensive analysis of the data from the studies paved a way of designing dual inhibitors to the proteins, on the basis of the chemical structures of ABT-737, which is a highly potent inhibitor to the Bcl-XL. The unique feature of this approach on designing the dual inhibitors to the anti-apoptotic proteins have also been brought into detail through a comparative analysis with a few existing strategies reported on the same line in the literature.