题名 | Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis |
作者 | |
发表日期 | 2023-07 |
发表期刊 | Journal of computer-aided molecular design 影响因子和分区 |
语种 | 英语 |
原始文献类型 | Journal Article |
关键词 | Allosteric communication network Drug resistance FGFR3 MD simulations Umbrella sampling |
其他关键词 | GENERAL FORCE-FIELD ; HISTOGRAM ANALYSIS METHOD ; ALLOSTERIC COMMUNICATION ; ISOFORM SELECTIVITY ; ACQUIRED-RESISTANCE ; SENSITIVITY ; AUTOMATION ; GEFITINIB ; EXTENSION ; INSIGHTS |
摘要 | FGFR3 kinase mutations are associated with a variety of malignancies, but FGFR3 mutant inhibitors have rarely been studied. Furthermore, the mechanism of pan-FGFR inhibitors resistance caused by kinase domain mutations is still unclear. In this study, we try to explain the mechanism of drug resistance to FGFR3 mutation through global analysis and local analysis based on molecular dynamics simulation, binding free energy analysis, umbrella sampling and community network analysis. The results showed that FGFR3 mutations caused a decrease in the affinity between drugs and FGFR3 kinase, which was consistent with the reported experimental results. Possible mechanisms are that mutations affect drug-protein affinity by altering the environment of residues near the hinge region where the protein binds to the drug, or by affecting the A-loop and interfering with the allosteric communication networks. In conclusion, we systematically elucidated the underlying mechanism of pan-FGFR inhibitor resistance caused by FGFR3 mutation based on molecular dynamics simulation strategy, which provided theoretical guidance for the development of FGFR3 mutant kinase inhibitors. |
资助项目 | MOE Key Laboratory of Tumor Molecular Biology[50411651-2020-4];the Guangdong Basic and Applied Basic Research Foundation[2021A1515011184];National Natural Science Foundation of China[81803580];National Natural Science Foundation of China[81402839];Natural Science Foundation of Zhejiang Province[LGF20B020001] |
出版者 | SPRINGER |
ISSN | 0920-654X |
EISSN | 1573-4951 |
卷号 | 37期号:7页码:325-338 |
DOI | 10.1007/s10822-023-00510-8 |
页数 | 14 |
WOS类目 | Biochemistry & Molecular Biology ; Biophysics ; Computer Science, Interdisciplinary Applications |
WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics ; Computer Science |
WOS记录号 | WOS:000998751800001 |
收录类别 | PUBMED ; SCIE ; EI ; SCOPUS |
在线发表日期 | 2023-06 |
EI入藏号 | 20232314190940 |
EI主题词 | Molecular dynamics |
EI分类号 | 641.1 Thermodynamics ; 801.4 Physical Chemistry |
URL | 查看原文 |
PubMed ID | 37269435 |
SCOPUSEID | 2-s2.0-85160820550 |
通讯作者地址 | [Li, Wulan]The First Affiliated Hospital,Wenzhou Medical University,Zhejiang,Wenzhou,325035,China ; [Chen, Qian]Future Health Laboratory,Innovation Center of Yangtze River Delta,Zhejiang University,Jiaxing,314102,China |
Scopus学科分类 | Drug Discovery;Computer Science Applications;Physical and Theoretical Chemistry |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.wmu.edu.cn/handle/3ETUA0LF/180638 |
专题 | 附属第一医院 药学院(分析测试中心) 眼视光学院(生物医学工程学院)、附属眼视光医院 |
通讯作者 | Chen, Qian; Li, Wulan |
作者单位 | 1.The First Affiliated Hospital,Wenzhou Medical University,Zhejiang,Wenzhou,325035,China; 2.Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine,Vision and Brain Health),Zhejiang,Wenzhou,325000,China; 3.School of Pharmaceutical Sciences,Wenzhou Medical University,Zhejiang,Wenzhou,325035,China; 4.The Eye Hospital,School of Ophthalmology & Optometry,Wenzhou Medical University,Wenzhou,325027,China; 5.Institute of Tissue Transplantation and Immunology,College of Life Science and Technology,Jinan University,Guangzhou,510632,China; 6.MOE Key Laboratory of Tumor Molecular Biology,Jinan University,Guangzhou,510632,China; 7.Future Health Laboratory,Innovation Center of Yangtze River Delta,Zhejiang University,Jiaxing,314102,China |
第一作者单位 | 附属第一医院; 药学院(分析测试中心) |
通讯作者单位 | 附属第一医院 |
第一作者的第一单位 | 附属第一医院 |
推荐引用方式 GB/T 7714 | Liu, Bo,Ding, Juntao,Liu, Yugang,et al. Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis[J]. Journal of computer-aided molecular design,2023,37(7):325-338. |
APA | Liu, Bo., Ding, Juntao., Liu, Yugang., Wu, Jianzhang., Wu, Xiaoping., ... & Li, Wulan. (2023). Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis. Journal of computer-aided molecular design, 37(7), 325-338. |
MLA | Liu, Bo,et al."Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis".Journal of computer-aided molecular design 37.7(2023):325-338. |
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