caa a22 4500 605511462 CHVBK 20210128100651.0 cr unu---uuuuu 210128e20150701xx s 000 0 eng 10.1007/s00894-015-2716-z doi (NATIONALLICENCE)springer-10.1007/s00894-015-2716-z Computationally unraveling how ceritinib overcomes drug-resistance mutations in ALK-rearranged lung cancer [Elektronische Daten] [Zhong Ni, Tian-Cheng Zhang] Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, has been implicated in the pathogenesis of several cancers. The small molecule ceritinib can overcome drug-resistance mutations that are observed in crizotinib-resistant patients, although the detailed mechanism for this ability of ceritinib remains elusive. Here, molecular dynamics (MD) simulations of six systems (including the apo ALK, the wild-type ALK-ceritinib complex, as well as four complexes of ceritinib with the I1171T, L1196M, S1206Y, and G1269A mutants of ALK, respectively) together with the subsequent molecular mechanics-generalized Born/surface area binding free energy calculations were performed to answer this question. Principal component analysis and domain cross-correlation analysis of MD trajectories revealed that ceritinib binding stabilized the conformational dynamics of both the wild-type and the four mutated ALKs as compared to the apo ALK. Moreover, the mutations had subtle effects on the conformation of ALK compared to that of the wild-type ALK. Importantly, binding free energy calculations demonstrated that, compared its effect on the wild-type ALK, ceritinib showed slightly increased potency towards the I1171T, L1196M, S1206Y, and G1269A mutants. Therefore, the binding of ceritinib to the four mutants can overcome crizotinib-resistant mutations. These data provide a structural and energetic explanation of how ceritinib overcomes mutation-induced drug resistance. Graphical Abstract Interactions between ceritinib and wild-type ALK Springer-Verlag Berlin Heidelberg, 2015 Anaplastic lymphoma kinase (ALK) nationallicence Molecular dynamics simulations nationallicence Ceritinib nationallicence MM-GBSA nationallicence Drug resistance nationallicence Ni Zhong Institute of Life Sciences, Jiangsu University, 212013, Zhenjiang, China aut Zhang Tian-Cheng International Joint Cancer Institute, The Second Military Medical University, 200433, Shanghai, China aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/7(2015-07-01), 1-10 1610-2940 21:7<1 2015 21 894 https://doi.org/10.1007/s00894-015-2716-z text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2716-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Ni Zhong Institute of Life Sciences, Jiangsu University, 212013, Zhenjiang, China aut NATIONALLICENCE 700 1- Zhang Tian-Cheng International Joint Cancer Institute, The Second Military Medical University, 200433, Shanghai, China aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/7(2015-07-01), 1-10 1610-2940 21:7<1 2015 21 894