Theoretical Study On The Binding Properties Of Inhibitors To Myeloid Cell Leukemia 1

The body develops normally,and the process of removing unnecessary or damaged cells is called apoptosis.Through cell proliferation and apoptosis,various tissue cells in the body maintain normal numbers and functions.Dysregulation of apoptosis often leads to the development of many diseases,and studies have found that dysregulation of apoptosis is an important marker of cancer development.Therefore,selectively activating the inherent apoptotic signals in cancer cells,restoring the blocked apoptotic pathways in cancer cells,and inducing apoptosis to remove cancerous cells has become a deeper and more durable approach to treat cancer.In the apoptosis mechanism,the B-cell lymphoma-2(Bcl-2)protein family plays a key regulatory role.Myeloid cell leukemia 1(Mcl-1)is an anti-apoptotic member of the Bcl-2 family proteins,that has emerged as a promising target for cancer treatment.Overexpression or up-regulation of Mcl-1 proteins has been identified in most cancer cells,which can lead to the evasion of apoptosis and is closely related to the resistance of anticancer therapies.In this paper,molecular dynamics(MD)simulations were used to explore the internal conformational changes of the protein caused by the binding of the inhibitor to Mcl-1 protein and its potential binding mechanism.Subsequently,correlation analysis and principal component analysis of the snapshots obtained from the equilibrium MD trajectories showed a significant effect of inhibitor binding on the internal dynamics motion pattern and conformational changes of the Mcl-1 protein.Meanwhile,the binding free energy of the inhibitor to Mcl-1 was calculated using the molecular mechanics-generalized Born surface area(MM-GBSA)method.The results showed that the calculated binding free energies were in good agreement with the experimental values and that electrostatic interactions and van der Waals interactions contributed higher energies in the binding of the inhibitor to Mcl-1.In order to further investigate the binding mode of the inhibitor to Mcl-1,a residue-based free energy decomposition approach was applied and it was concluded that residues F228,M231,M250,V253,R263,L267 and F270 provide the major energetic contributions to the binding of the inhibitor to Mcl-1 protein.The findings from the present study might provide valuable guidelines for the design of novel Mcl-1 inhibitors and provide a powerful reference for improving the specificity and effectiveness of a new generation of chemotherapeutic agents.