2. Academic Validation
  3. Structure-Based Ligand Discovery Targeting the Transmembrane Domain of Frizzled Receptor FZD7

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

  • J Med Chem. 2023 Sep 14;66(17):11855-11868. doi: 10.1021/acs.jmedchem.2c01795.
Cuixia Li 1 2,  Yiran Wu 1,  Wenli Wang 3,  Lu Xu 1,  Yan Zhou 4,  Yang Yue 1,  Tingting Wu 1,  Meifang Yang 5,  Yanli Qiu 1 2 5,  Minhao Huang 3,  Fangfang Zhou 1,  Yiqing Zhou 6,  Piliang Hao 2,  Zhixiong Lin 3,  Ming-Wei Wang 4 7,  Suwen Zhao 1 2,  Dehua Yang 4,  Fei Xu 1 2,  Houchao Tao 5
Affiliations

Affiliations

  • 1 iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 3 Shenzhen Jingtai Technology Co., Ltd. (XtalPi), Floor 3, Sf Industrial Plant, No. 2 Hongliu Road, Fubao Community, Fubao Street, Futian District, Shenzhen 518045, China.
  • 4 The National Center for Drug Screening, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
  • 5 Shanghai Frontiers Science Center of TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 6 School of Biotechnology and Food Engineering, Changshu Institute of Technology, Suzhou 215500, China.
  • 7 Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
PMID: 37669317 DOI: 10.1021/acs.jmedchem.2c01795
Abstract

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 small-molecule ligand discovery by targeting TMD. From the ChemDiv library with ∼1.6 million compounds, we identified compound F7H as an antagonist of FZD7 with an IC50 at 1.25 ± 0.38 μM. 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-156095
    99.42%, FZD7 Inhibitor
    Wnt