Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis

doi:10.1007/s10822-023-00510-8

科研成果详情

题名	Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis
作者	Liu, Bo 1,2,3; Ding, Juntao1,2,3; Liu, Yugang 1,3; Wu, Jianzhang2,3,4; Wu, Xiaoping 5,6; Chen, Qian 7; Li, Wulan1,2,3
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.