A computational perspective for tailor-made selective Mcl-1 and Bcl-XL inhibitors

In view of the crucial role of Mcl-1 in tumor survival and resistance as well as the importance of BclXL in platelets homeostasis, an appropriate tuning of binding selectivity between Mcl-1 and Bcl-XL is crucial to discover safer anticancer candidates. In this respect, comprehensive computational approaches such as protein comparison, molecular docking, molecular dynamics simulations, mutagenesis, and density functional theory (DFT) calculation were applied to elucidate the different binding modes between highly selective Mcl-1 and Bcl-XL inhibitors. It was found that although Mcl-1 and Bcl-XL shared high sequence homology in their active pockets, the P2 pocket of Mcl-1 merged with P1 and P3, whereas the P3 pocket bridged through the P2 and P4 pocket of Bcl-XL. Accordingly, the key residues that determined the selectivity between Mcl-1 and Bcl-XL included Asn260, Arg263, and Phe270 in Mcl-1, and Glu96, Ser106, Leu108, Asn136, and Arg139 in Bcl-XL. In particular, Phe270 served as a major contributor to the p-pstacking interactions between Mcl-1 and its selective inhibitor, whereas Tyr195 was the key residue establishing the p-pstacking between Bcl-XL and its selective inhibitor. Collectively, these data shed promising light in depicting the selective mechanisms between Mcl-1 and Bcl-XL, which would lay a solid foundation for the future designing of the selective inhibitors in the discovery and optimization of a compound on the path toward developing future anticancer drugs. (c) 2021 Elsevier B.V. All rights reserved.

Automated summary

The selective binding mechanism between Mcl-1 and Bcl-XL depends on key residues, particularly Phe270 in Mcl-1 and Tyr195 in Bcl-XL. These findings are of significant importance for the discovery of safer anticancer drug candidates.