Abstract:
In order to investigate the effect of anaplastic lymphoma kinase (ALK) F1174V mutation on the interaction of ALK and crizotinib, we performed molecular dynamics (MD) simulations, essential dynamics (ED) analyses and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations on wild-type (WT) and mutant ALK-crizotinib complex. Our MD simulations and ED analysis indicate that the F1174V mutation can decrease the flexibility of ALK, especially for the crizotinib binding pocket, which can result in decreased kinetics of drug entrance and egress. The MM-PBSA calculations demonstrate that the mutant exhibits weakened cofactor binding affinity with crizotinib in comparison with WT. Comparison between representative structures of the constructed free energy landscape (FEL) of WT and mutant suggests that the F1174V mutation significantly changes the ALK structure, thereby weakens the interactions with crizotinib by shrinking the P-loop and narrowing the pocket volume. Our study sheds light on the mechanism of ALK targeted drug resistance, providing insight into the design of potent and effective drug for non-small cell lung cancer.