Combinatorial Pharmacophore-Based 3D-QSAR Analysis and Virtual Screening of FGFR1 Inhibitors

doi:10.3390/ijms160613407

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Combinatorial Pharmacophore-Based 3D-QSAR Analysis and Virtual Screening of FGFR1 Inhibitors
	Zhou, Nannan 1,2; Xu, Yuan 3; Liu, Xian 3; Wang, Yulan 3; Peng, Jianlong 3; Luo, Xiaomin3 ; Zheng, Mingyue3 ; Chen, Kaixian3 ; Jiang, Hualiang1,2,3
刊名	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
	2015-06
卷号	16 期号:6 页码:13407-13426
ISSN号	1422-0067
DOI	10.3390/ijms160613407
文献子类	Article
英文摘要	The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays crucial roles in cell proliferation, angiogenesis, migration, and survival. Aberration in FGFRs correlates with several malignancies and disorders. FGFRs have proved to be attractive targets for therapeutic intervention in cancer, and it is of high interest to find FGFR inhibitors with novel scaffolds. In this study, a combinatorial three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed based on previously reported FGFR1 inhibitors with diverse structural skeletons. This model was evaluated for its prediction performance on a diverse test set containing 232 FGFR inhibitors, and it yielded a SD value of 0.75 pIC(50) units from measured inhibition affinities and a Pearson's correlation coefficient R-2 of 0.53. This result suggests that the combinatorial 3D-QSAR model could be used to search for new FGFR1 hit structures and predict their potential activity. To further evaluate the performance of the model, a decoy set validation was used to measure the efficiency of the model by calculating EF (enrichment factor). Based on the combinatorial pharmacophore model, a virtual screening against SPECS database was performed. Nineteen novel active compounds were successfully identified, which provide new chemical starting points for further structural optimization of FGFR1 inhibitors.
资助项目	Hi-Tech Research and Development Program of China[2014AA01A302] ; Hi-TECH Research and Development Program of China[2012AA020308] ; Hi-Tech Research and Development Program of China[2012AA01A305] ; National Natural Science Foundation of China[81430084] ; Ministry of Science and Technology of China[2015CB910304] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2014ZX09507002]
WOS关键词	GROWTH-FACTOR RECEPTOR ; TYROSINE KINASE INHIBITOR ; 3D QSAR ; SOLID TUMORS ; IDENTIFICATION ; DESIGN ; CANCER ; SETS ; OPPORTUNITIES ; CHALLENGES
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
语种	英语
出版者	MDPI AG
WOS记录号	WOS:000357492800085
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276501]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Zheng, Mingyue
作者单位	1.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Bilolgy, Shanghai 200237, Peoples R China; 2.E China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Nannan,Xu, Yuan,Liu, Xian,et al. Combinatorial Pharmacophore-Based 3D-QSAR Analysis and Virtual Screening of FGFR1 Inhibitors[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2015,16(6):13407-13426.
APA	Zhou, Nannan.,Xu, Yuan.,Liu, Xian.,Wang, Yulan.,Peng, Jianlong.,...&Jiang, Hualiang.(2015).Combinatorial Pharmacophore-Based 3D-QSAR Analysis and Virtual Screening of FGFR1 Inhibitors.INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,16(6),13407-13426.
MLA	Zhou, Nannan,et al."Combinatorial Pharmacophore-Based 3D-QSAR Analysis and Virtual Screening of FGFR1 Inhibitors".INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 16.6(2015):13407-13426.