Insight on mutation-induced resistance to anaplastic lymphoma kinase inhibitor ceritinib from molecular dynamics simulations.

He MY, Li WK, Meiler J, Zheng QC, Zhang HX
Biopolymers. 2019 110 (2): e23257

PMID: 30664251 · DOI:10.1002/bip.23257

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.

© 2019 Wiley Periodicals, Inc.

MeSH Terms (13)

Adenosine Triphosphate Anaplastic Lymphoma Kinase Binding Sites Drug Resistance, Neoplasm Humans Molecular Dynamics Simulation Mutagenesis, Site-Directed Neoplasms Principal Component Analysis Protein Kinase Inhibitors Protein Structure, Tertiary Pyrimidines Sulfones

Connections (1)

This publication is referenced by other Labnodes entities: