Indexed by:期刊论文

Date of Publication:2016-04-01

Journal:CHEMICAL BIOLOGY & DRUG DESIGN

Included Journals:SCIE、PubMed、Scopus

Volume:87

Issue:4

Page Number:551-561

ISSN No.:1747-0277

Key Words:binding free energy; conformation change; inhibitor; Mcl-1; molecular dynamics simulation

Abstract:Inhibition of interactions between Mcl-1 and proapoptotic proteins is considered to be a therapeutic strategy to induce apoptosis in cancer cells. Here, we adopted molecular dynamics simulation with molecular mechanics-Poisson Boltzmann/surface area method (MM-PB/SA) to study the inhibition mechanism of three Mcl-1 inhibitors, compounds 1, 2 and 3. Analysis of energy components shows that the better binding free energy of compound 3 than compounds 1 and 2 is attributable to the van der Waals energy (E-vdw) and non-polar solvation energy (G(np)) upon binding. In addition to the excellent agreement with previous experimentally determined affinities, our simulation results further show a bend of helix 4 on Mcl-1 upon compound 3 binding, which is driven by hydrophobic interaction with residue Val(253), leading to a narrowed BH3-binding groove to impede Puma(BH3) binding. The computational result is consistent with our competitive isothermal titration calorimetry (ITC) assays, which shows that the competitive ability of compound 3 toward Mcl-1/Puma(BH3) complex is improved beyond its direct binding affinity toward Mcl-1 itself, and compound 3 exhibits much more efficiency to compete with Puma(BH3) than compound 2. Our study provides a new strategy to improve inhibitory activity on Mcl-1 based on the conformational dynamic change.