title: Fragment-based strategy for structural optimization in combination with 3D-QSAR.
abstract: Fragment-based drug design has emerged as an important methodology for lead discovery and drug design. Different with other studies focused on fragment library design and active fragment identification, a fragment-based strategy was developed in combination with three-dimensional quantitative structure-activity relationship (3D-QSAR) for structural optimization in this study. Based on a validated scaffold or fragment hit, a series of structural optimization was conducted to convert it to lead compounds, including 3D-QSAR modelling, active site analysis, fragment-based structural optimization and evaluation of new molecules. 3D-QSAR models and active site analysis provided sufficient information for confirming the SAR and pharmacophoric features for fragments. This strategy was evaluated through the structural optimization on a c-Met inhibitor scaffold 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one, which resulted in an c-Met inhibitor with high inhibitory activity. Our study suggested the effectiveness of this fragment-based strategy and the druggability of our newly explored active region. The reliability of this strategy indicated it could also be applied to facilitate lead optimization of other targets.
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China, 0444909yuan@gmail.com.
authors.forename: Haoliang
authors.initials: H
authors.lastname: Yuan
authors.forename: Wenting
authors.initials: W
authors.lastname: Tai
authors.forename: Shihe
authors.initials: S
authors.lastname: Hu
authors.forename: Haichun
authors.initials: H
authors.lastname: Liu
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sihui
authors.initials: S
authors.lastname: Yao
authors.forename: Ting
authors.initials: T
authors.lastname: Ran
authors.forename: Shuai
authors.initials: S
authors.lastname: Lu
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Ke
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiong
authors.forename: Jinxing
authors.initials: J
authors.lastname: Xu
authors.forename: Yadong
authors.initials: Y
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
mesh_terms: D001567:Benzocycloheptenes / Q000737:chemistry*; D020134:Catalytic Domain; D015195:Drug Design; D006801:Humans; D008962:Models, Theoretical; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D000076202:c-Mer Tyrosine Kinase
chemical_list: C561052:5H-benzo(4,5)cyclohepta(1,2-b)pyridin-5-one; D001567:Benzocycloheptenes; D011518:Proto-Oncogene Proteins; D011725:Pyridines; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase