Anaplastic lymphoma kinase (ALK) has been regarded as an essential target for the treatment of nonsmall cell lung cancer (NSCLC). However, the emergence of the G1202R solvent front mutation that confers resistance to the drugs was reported for the first as well as the second generation ALK inhibitors. It was thought that the G1202R solvent front mutation might hinder the drug binding. In this study, a different fact could be clarified by multiple molecular modeling methodologies through a structural analogue of ceritinib (compound 10, Cpd-10) that is reported to be a potent inhibitor against the G1202R mutation. Herein, molecular docking, accelerated molecular dynamics (aMD) simulations in conjunction with principal component analysis (PCA), and free energy map calculations were used to produce reasonable and representative initial conformations for the conventional MD simulations. Compared with Cpd-10, the binding specificity of ceritinib between ALK wild-type (ALK^WT) and ALK G1202R (ALK^G1202R) are primarily controlled by the conformational change of the P-loop- and A-loop-induced energetic redistributions, and the variation is nonpolar interactions, as indicated by conventional MD simulations, PCA, dynamic cross-correlation map (DCCM) analysis, and free energy calculations. Furthermore, the umbrella sampling (US) simulations were carried out to make clear the principle of the dissociation processes of ceritinib and Cpd-10 toward ALK^WT and ALK^G1202R. The calculation results suggest that Cpd-10 has similar dissociation processes from both ALK^WT and ALK^G1202R, but ceritinib is more easily dissociated from ALK^G1202R than from ALK^WT, thus less residence time is responsible for the ceritinib resistance. Our results suggest that both the binding specificity and the drug residence time should be emphasized in rational drug design to overcome the G1202R solvent front mutation of ALK resistance.

	Year	Citations

About