Structure-Based Ligand Discovery Targeting the Transmembrane Domain of Frizzled Receptor FZD7,Journal of Medicinal Chemistry

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Structure-Based Ligand Discovery Targeting the Transmembrane Domain of Frizzled Receptor FZD7
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-09-05 , 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

Affiliation

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.

中文翻译：

针对卷曲受体 FZD7 跨膜域的基于结构的配体发现

尽管卷曲受体 (FZD) 在介导胚胎发育和组织稳态中 Wnt 信号传导方面发挥着重要作用，但针对 FZD 的配体却很少。已经开发出一些抗体和肽调节剂，主要与 FZD 家族保守的胞外富含半胱氨酸结构域结合，而跨膜结构域 (TMD) 中的典型结合位点还远远没有得到充分解决。基于FZDs的最新结构，我们探索了靶向TMD的小分子配体发现。从包含约 160 万种化合物的 ChemDiv 文库中，我们鉴定出化合物 F7H 是 FZD7 的拮抗剂，其 IC ₅₀为 1.25 ± 0.38 μM。围绕这一成果，结构解剖研究与分子对接、分子动力学模拟和自由能微扰计算等计算研究一起，定义了具有关键残基识别的结合口袋。我们的结果揭示了配体识别的结构基础，并证明了 FZD7-TMD 结构引导配体发现的可行性。

更新日期：2023-09-05

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