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

文献类型：期刊论文

作者Li, Cuixia2,5; Wu, Yiran5; Wang, Wenli3; Xu, Lu5; Zhou, Yan4; Yue, Yang5; Wu, Tingting5; Yang, Meifang6; Qiu, Yanli2,5,6; Huang, Minhao3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-09-05
页码14
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c01795
通讯作者Zhao, Suwen(zhaosw@shanghaitech.edu.cn) ; Yang, Dehua(dhyang@simm.ac.cn) ; Xu, Fei(xufei@shanghaitech.edu.cn) ; Tao, Houchao(houchao@shutcm.edu.cn)
英文摘要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.
WOS关键词PROTEIN-COUPLED RECEPTORS ; WNT RECEPTOR ; ACCURATE DOCKING ; GLIDE ; PATHWAY
资助项目National Key R&D Program of China[2018YFA0507000]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001062591800001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/306143]  
专题中国科学院上海药物研究所
通讯作者Zhao, Suwen; Yang, Dehua; Xu, Fei; Tao, Houchao
作者单位1.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, 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.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
6.Shanghai Univ Tradit Chinese Med, Innovat Res Inst Tradit Chinese Med, Shanghai Frontiers Sci Ctr TCM Chem Biol, Shanghai 201203, Peoples R China
7.Changshu Inst Technol, Sch Biotechnol & Food Engn, Suzhou 215500, Peoples R China
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,2023:14.
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,14.
MLA Li, Cuixia,et al."Structure-Based Ligand Discovery Targeting the Transmembrane Domain of Frizzled Receptor FZD7".JOURNAL OF MEDICINAL CHEMISTRY (2023):14.

入库方式： OAI收割

来源：上海药物研究所

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