Study of the dynamics of Ceritinib in complex with common variants of anaplastic lymphoma kinase

Abstract

ABSTRACT Anaplastic lymphoma kinase, a transmembrane receptor tyrosine kinase belongs to the insulin receptor superfamily. Genetic aberrations including mutation, amplification, and gene fusion have led to its involvement in the development of cancer in patients and have also been approved for targeted therapy by Food and Drug Administration. Mutations in its kinase domain have resulted in resistance to targeted therapy. In the present study, using molecular dynamics simulations we explore the mechanism of resistance of the ALK inhibitor-Ceritinib with Phenylalanine variant at position 1174 while comparing it with the wild type and other reported mutants. We observed that binding of Ceritinib to the Phenylalanine 1174 mutant results in elevated fluctuations in residues which are component of the adenosine triphosphate binding pocket. Residues of P loop, β3 strand and αC Helix undergo anti correlated motions with respect to the αD, αE helix, component amino acids of β6-β7 strands and their interconnecting loop. This anti-correlated motion of the residues around the binding pocket results in the elevated deviations of the bound Ceritinib. Molecular mechanics-generalized born surface area free energy of binding analysis reveals comparatively weak binding of the Ceritinib to this variant compared to other forms of ALK kinase studied.