3 research outputs found
Molecular Mechanism Behind the Resistance of the G1202R-Mutated Anaplastic Lymphoma Kinase to the Approved Drug Ceritinib
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<sup>WT</sup>)
and ALK G1202R (ALK<sup>G1202R</sup>) 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<sup>WT</sup> and ALK<sup>G1202R</sup>. The calculation results suggest
that Cpd-10 has similar dissociation processes from both ALK<sup>WT</sup> and ALK<sup>G1202R</sup>, but ceritinib is more easily dissociated
from ALK<sup>G1202R</sup> than from ALK<sup>WT</sup>, 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
Libocedus macrolepis Benth. et Hook. f.
原著和名: セウナンボク科名: ヒノキ科 = Cupressaceae採集地: 千葉県 安房郡 天津小湊町 (安房 天津小湊町)採集日: 1963/12/19採集者: 萩庭丈壽整理番号: JH028633国立科学博物館整理番号: TNS-VS-978633備考: 梢楠
Additional file 1: Table S1. of CMISG1701: a multicenter prospective randomized phase III clinical trial comparing neoadjuvant chemoradiotherapy to neoadjuvant chemotherapy followed by minimally invasive esophagectomy in patients with locally advanced resectable esophageal squamous cell carcinoma (cT3-4aN0-1M0) (NCT03001596)
Treatment schedule. (DOCX 20 kb