title: Combinatorial Pharmacophore-Based 3D-QSAR Analysis and Virtual Screening of FGFR1 Inhibitors.
abstract: 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 pIC50 units from measured inhibition affinities and a Pearson's correlation coefficient R2 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.
authors.affiliation: State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of Chemical Bilolgy, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. nannanzhou0912@163.com.
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. xu_yuan88@163.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. xmluo@simm.ac.cn.
authors.forename: Xian
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. ylwang@simm.ac.cn.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. pjlxsda@163.com.
authors.forename: Jianlong
authors.initials: J
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. xmluo@simm.ac.cn.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. myzheng@simm.ac.cn.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. kxchen@simm.ac.cn.
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of Chemical Bilolgy, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. hljiang@simm.ac.cn.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. hljiang@simm.ac.cn.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D062126:Databases, Chemical; D055808:Drug Discovery; D004797:Enzyme-Linked Immunosorbent Assay; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D015151:Immunoblotting; D008958:Models, Molecular; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D004364:Pharmaceutical Preparations; D017468:Receptors, Fibroblast Growth Factor
keywords: FGFR1 inhibitors; combinatorial 3D-QSAR; pharmacophore; virtual screening