A molecular dynamics investigation on the crizotinib resistance mechanism of C1156Y mutation in ALK.
Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor that has recently been approved in the US for the treatment of non-small cell lung carcinoma (NSCLC). Despite its outstanding safety and efficacy, several resistant mutations against crizotinib have been detected in the treatment of NSCLC. However, in contrast to the widely accepted mechanism of steric hindrance by mutations at the active site, the mechanism by which the C1156Y non-active site mutation confers resistance against crizotinib remains unclear. In the present study, the resistance mechanism of C1156Y in ALK was investigated using molecular dynamics simulations. The results suggest that despite the non-active site mutation, C1156Y causes the dislocation of crizotinib as well as the indirect conformational changes in the binding cavity, which results in a marked decrease in the van der Waals and electrostatic interactions between crizotinib and ALK. The obtained results provide a detailed explanation of the resistance caused by C1156Y and may give a vital clue for the design of drugs to combat crizotinib resistance.
Shandong University of Technology, Zibo 255049, PR China.
Hui-Yong
HY
Sun
Feng-Qin
FQ
Ji
D019943:Amino Acid Substitution; D000077548:Anaplastic Lymphoma Kinase; D020134:Catalytic Domain / Q000235:genetics; D000077547:Crizotinib; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D014443:Tyrosine / Q000737:chemistry / Q000235:genetics
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D014443:Tyrosine; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D003545:Cysteine