Molecular Modeling of ALK L1198F and/or G1202R Mutations to Determine Differential Crizotinib Sensitivity

Scientific Reports
Yu-Chung ChuangChia-Ning Yang

Abstract

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been recognized as a therapeutic target for EML4-ALK fusion-positive nonsmall cell lung cancer (NSCLC) treatment using type I kinase inhibitors such as crizotinib to take over the ATP binding site. According to Shaw's measurements, ALK carrying G1202R mutation shows reduced response to crizotinib (IC50 = 382 nM vs. IC50 = 20 nM for wild-type), whereas L1198F mutant is more responsive (IC50 = 0.4 nM). Interestingly, the double mutant L1198F/G1202R maintains a similar response (IC50 = 31 nM) to the wild-type. Herein we conducted molecular modeling simulations to elucidate the varied crizotinib sensitivities in three mutants carrying L1198F and/or G1202R. Both L1198 and G1202 are near the ATP pocket. Mutation G1202R causes steric hindrance that blocks crizotinib accessibility, which greatly reduces efficacy, whereas mutation L1198F enlarges the binding pocket entrance and hydrophobically interacts with crizotinib to enhance sensitivity. With respect to the double mutant L1198F/G1202R, F1198 indirectly pulls R1202 away from the binding entrance and consequently alleviates the steric obstacle introduced by R1202. These results demonstrated how the mutated residu...Continue Reading

References

Nov 1, 1983·Proceedings of the National Academy of Sciences of the United States of America·B Brooks, M Karplus
Mar 30, 2001·The Journal of Biological Chemistry·G E StoicaA Wellstein
Jul 18, 2002·The Journal of Biological Chemistry·Gerald E StoicaAnton Wellstein
Oct 24, 2002·Journal of Computational Chemistry·Araz JakalianChristopher I Bayly
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Dec 12, 2007·The Journal of Biological Chemistry·Carmen J TartariCarlo Gambacorti-Passerini
Sep 13, 2008·Proceedings of the National Academy of Sciences of the United States of America·Alexandr P KornevLynn F Ten Eyck
Sep 17, 2008·Nature Structural & Molecular Biology·Mohammad AzamGeorge Q Daley
Jul 17, 2010·The Biochemical Journal·Christian C LeeGlen Spraggon
Sep 29, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Johannes M HeuckmannRoman K Thomas
Dec 4, 2012·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Robert Roskoski
Mar 5, 2013·Drug Discovery Today·Albert C PanDavid E Shaw
Jan 21, 2014·Journal of Chemical Information and Modeling·Jagdish Suresh PatelAndrea Cavalli
Mar 29, 2014·Cancer Discovery·Luc FribouletJeffrey A Engelman
Apr 17, 2014·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Sai-Hong Ignatius OuVincent A Miller
Oct 10, 2014·Journal of Chemical Information and Modeling·Anna Maria Capelli, Gabriele Costantino
Dec 9, 2014·ACS Chemical Biology·Michael Tong, Markus A Seeliger
May 16, 2015·Trends in Pharmacological Sciences·Peng WuMads H Clausen
May 20, 2015·Journal of Molecular Graphics & Modelling·Cong-min KangYing-tao Lv
Jul 27, 2015·Drug Discovery Today·Peng WuMads H Clausen
Nov 4, 2015·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Robert Roskoski
Nov 17, 2015·Journal of Medicinal Chemistry·John M HatcherNathanael S Gray
Jun 14, 2011·Journal of Chemical Theory and Computation·Jean-François St-PierreAlex Bunker
Jan 1, 2007·Journal of Chemical Theory and Computation·John D ChoderaKen A Dill
Dec 18, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Alexander DrilonMonika A Davare
Dec 25, 2015·The New England Journal of Medicine·Alice T ShawJeffrey A Engelman
Aug 31, 2016·Annals of Oncology : Official Journal of the European Society for Medical Oncology·B Hallberg, R H Palmer
Jan 13, 2017·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Robert Roskoski
Aug 3, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Lars D EngstromJames G Christensen
Nov 14, 2017·Current Opinion in Structural Biology·Neil J BruceRebecca C Wade
Jan 13, 2018·Journal of Cellular Biochemistry·Muyang HeHongxing Zhang

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X-ray
pulls down

Software Mentioned

Antechamber
AMBER14
AMBER
GBSA
MM
WHAM

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