Theoretical Study on the Binding Properties of Inhibitors to Myeloid Cell Leukemia 1

Abstract

Myeloid leukemia 1 (Mcl-1) is a key anti-apoptotic member of the Bcl-2 protein family, and its overexpression or upregulation has been found in numerous cancer cells, which not only leads to tumorigenesis mediated by apoptotic escape modality, but also causes resistance to multiple subsequent anti-cancer therapies. The development of small molecule inhibitors that specifically target Mcl-1 and restore the blocked apoptotic pathway in cancer cells has emerged as a realistic solution for oncology drug design. Therefore, an in-depth study of the mechanism of action of inhibitors with Mcl-1 is important for the design of efficient drugs targeting Mcl-1. In this study, using molecular dynamics (MD) simulations, correlation analysis and principal component analysis, we revealed that the binding of inhibitors significantly altered the kinetic behavior of Mcl-1 and led to a conformational rearrangement of Mcl-1. Subsequently, the molecular mechanics-generalized Born surface area (MM-GBSA) method was used to further explore the binding ability of different inhibitors to Mcl-1, and the results showed that the calculated binding free energies agreed well with the experimental values, and van der Waals interactions and electrostatic interactions provided the main favorable contribution in the binding of inhibitors to Mcl-1. Furthermore, the interaction analysis showed a large number of hydrophobic interactions and hydrogen bonding between the inhibitor and Mcl-1. Finally, the residues F228, M231, M250, V253, T266, L267 and F270 and R263 were identified by residue-based free energy decomposition calculations to provide important energetic contributions to the binding of the inhibitor to Mcl-1 and could be key targets for the design of Mcl-1 inhibitors.