Structure-Based Ligand Discovery Targeting the Transmembrane Domain of Frizzled Receptor FZD7

doi:10.1021/acs.jmedchem.2c01795

KMS > iHuman研究所

	Structure-Based Ligand Discovery Targeting the Transmembrane Domain of Frizzled Receptor FZD7
	Li, Cuixia1,2 ; Wu, Yiran1 ; Wang, Wenli 3; Xu, Lu1 ; Zhou, Yan 4; Yue, Yang1 ; Wu, Tingting1 ; Yang, Meifang 5; Qiu, Yanli1,2,5 ; Huang, Minhao 3; Zhou, Fangfang1 ; Zhou, Yiqing 6; Hao, Piliang2 ; Lin, Zhixiong 3; Wang, Ming-Wei 4,7; Zhao, Suwen1,2 ; Yang, Dehua 4; Xu, Fei1,2 ; Tao, Houchao 5
	2023-09-05
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN	0022-2623
EISSN	1520-4804
发表状态	已发表
DOI	10.1021/acs.jmedchem.2c01795
摘要	Despite the essential roles of Frizzled receptors (FZDs) in mediating Wnt signaling in embryonic development and tissue homeostasis, ligands targeting FZDs are rare. A few antibodies and peptide modulators have been developed that mainly bind to the family-conserved extracellular cysteine-rich domain of FZDs, while the canonical binding sites in the transmembrane domain (TMD) are far from sufficiently addressed. Based on the recent structures of FZDs, we explored smallmolecule ligand discovery by targeting TMD. From the ChemDiv library with similar to 1.6 million compounds, we identified compound F7H as an antagonist of FZD7 with an IC50 at 1.25 +/- 0.38 mu M. Focusing on this hit, the structural dissection study, together with computing studies such as molecular docking, molecular dynamics simulation, and free energy perturbation calculations, defined the binding pocket with key residue recognition. Our results revealed the structural basis of ligand recognition and demonstrated the feasibility of structure-guided ligand discovery for FZD7-TMD.
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收录类别	SCI
语种	英语
资助项目	National Key R&D Program of China[2018YFA0507000]
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:001062591800001
出版者	AMER CHEMICAL SOC
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/331106
专题	iHuman研究所生命科学与技术学院 iHuman研究所_特聘教授组_Kurt Wuthrich组 iHuman研究所_公共科研平台_IT平台 iHuman研究所_公共科研平台_动物细胞培养和蛋白纯化平台生命科学与技术学院_公共科研平台_组学分析平台 iHuman研究所_PI研究组_徐菲组 iHuman研究所_PI研究组_赵素文组生命科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Zhao, Suwen; Yang, Dehua; Xu, Fei; Tao, Houchao
作者单位	1.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 3.Shenzhen Jingtai Technol Co Ltd XtalPi, Shenzhen 518045, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 5.Shanghai Univ Tradit Chinese Med, Innovat Res Inst Tradit Chinese Med, Shanghai Frontiers Sci Ctr TCM Chem Biol, Shanghai 201203, Peoples R China 6.Changshu Inst Technol, Sch Biotechnol & Food Engn, Suzhou 215500, Peoples R China 7.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China
第一作者单位	iHuman研究所; 生命科学与技术学院
通讯作者单位	iHuman研究所; 生命科学与技术学院
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Li, Cuixia,Wu, Yiran,Wang, Wenli,et al. Structure-Based Ligand Discovery Targeting the Transmembrane Domain of Frizzled Receptor FZD7[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023.
APA	Li, Cuixia.,Wu, Yiran.,Wang, Wenli.,Xu, Lu.,Zhou, Yan.,...&Tao, Houchao.(2023).Structure-Based Ligand Discovery Targeting the Transmembrane Domain of Frizzled Receptor FZD7.JOURNAL OF MEDICINAL CHEMISTRY.
MLA	Li, Cuixia,et al."Structure-Based Ligand Discovery Targeting the Transmembrane Domain of Frizzled Receptor FZD7".JOURNAL OF MEDICINAL CHEMISTRY (2023).