Computationally unraveling how ceritinib overcomes drug-resistance mutations in ALK-rearranged lung cancer
| LEADER | caa a22 4500 | ||
|---|---|---|---|
| 001 | 605511462 | ||
| 003 | CHVBK | ||
| 005 | 20210128100651.0 | ||
| 007 | cr unu---uuuuu | ||
| 008 | 210128e20150701xx s 000 0 eng | ||
| 024 | 7 | 0 | |a 10.1007/s00894-015-2716-z |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s00894-015-2716-z | ||
| 245 | 0 | 0 | |a Computationally unraveling how ceritinib overcomes drug-resistance mutations in ALK-rearranged lung cancer |h [Elektronische Daten] |c [Zhong Ni, Tian-Cheng Zhang] |
| 520 | 3 | |a 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 | |
| 540 | |a Springer-Verlag Berlin Heidelberg, 2015 | ||
| 690 | 7 | |a Anaplastic lymphoma kinase (ALK) |2 nationallicence | |
| 690 | 7 | |a Molecular dynamics simulations |2 nationallicence | |
| 690 | 7 | |a Ceritinib |2 nationallicence | |
| 690 | 7 | |a MM-GBSA |2 nationallicence | |
| 690 | 7 | |a Drug resistance |2 nationallicence | |
| 700 | 1 | |a Ni |D Zhong |u Institute of Life Sciences, Jiangsu University, 212013, Zhenjiang, China |4 aut | |
| 700 | 1 | |a Zhang |D Tian-Cheng |u International Joint Cancer Institute, The Second Military Medical University, 200433, Shanghai, China |4 aut | |
| 773 | 0 | |t Journal of Molecular Modeling |d Springer Berlin Heidelberg |g 21/7(2015-07-01), 1-10 |x 1610-2940 |q 21:7<1 |1 2015 |2 21 |o 894 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s00894-015-2716-z |q text/html |z Onlinezugriff via DOI |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s00894-015-2716-z |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Ni |D Zhong |u Institute of Life Sciences, Jiangsu University, 212013, Zhenjiang, China |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Zhang |D Tian-Cheng |u International Joint Cancer Institute, The Second Military Medical University, 200433, Shanghai, China |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Molecular Modeling |d Springer Berlin Heidelberg |g 21/7(2015-07-01), 1-10 |x 1610-2940 |q 21:7<1 |1 2015 |2 21 |o 894 | ||