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Insight on mutation‐induced resistance to anaplastic lymphoma kinase inhibitor ceritinib from molecular dynamics simulations
Author(s) -
He MuYang,
Li WeiKang,
Meiler Jens,
Zheng QingChuan,
Zhang HongXing
Publication year - 2019
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.23257
Subject(s) - anaplastic lymphoma kinase , ceritinib , chemistry , mutagenesis , molecular dynamics , mutation , drug resistance , mutant , alk inhibitor , cancer research , biochemistry , biophysics , genetics , biology , computational chemistry , gene , medicine , surgery , pleural effusion , malignant pleural effusion
Ceritinib, an advanced anaplastic lymphoma kinase (ALK) next‐generation inhibitor, has been proved excellent antitumor activity in the treatment of ALK‐associated cancers. However, the accumulation of acquired resistance mutations compromise the therapeutic efficacy of ceritinib. Despite abundant mutagenesis data, the structural determinants for reduced ceritinib binding in mutants remains elusive. Focusing on the G1123S and F1174C mutations, we applied molecular dynamics (MD) simulations to study possible reasons for drug resistance caused by these mutations. The MD simulations predict that the studied mutations allosterically impact the configurations of the ATP‐binding pocket. An important hydrophobic cluster is identified that connects P‐loop and the αC‐helix, which has effects on stabilizing the conformation of ATP‐binding pocket. It is suggested, in this study, that the G1123S and F1174C mutations can induce the conformational change of P‐loop thereby causing the reduced ceritinib affinity and causing drug resistance.