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Updated: Jul 17, 2025
08:49
Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
322
Structure-Based Ligand Discovery Targeting the Transmembrane Domain of Frizzled Receptor FZD7
Cuixia Li1,2, Yiran Wu1, Wenli Wang3
1iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
Journal of Medicinal Chemistry
|September 5, 2023
Summary
Researchers identified a novel small molecule, F7H, that acts as an antagonist for Frizzled 7 (FZD7) by targeting its transmembrane domain. This discovery opens new avenues for structure-guided drug development for Wnt signaling pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Frizzled receptors (FZDs) are crucial for Wnt signaling in development and homeostasis.
- Targeting FZDs is challenging due to limited ligands, especially for the transmembrane domain (TMD).
Purpose of the Study:
- To explore small-molecule ligand discovery targeting the FZD transmembrane domain.
- To identify and characterize antagonists for Frizzled 7 (FZD7).
Main Methods:
- Screening of the ChemDiv compound library against FZD7.
- Structure-guided drug design including molecular docking, molecular dynamics, and free energy perturbation calculations.
- Biochemical assays to determine inhibitory concentration (IC50).
Main Results:
- Identified F7H as an antagonist of FZD7 with an IC50 of 1.25 ± 0.38 μM.
- Defined the binding pocket and key residue interactions within the FZD7 TMD.
- Elucidated the structural basis for ligand recognition.
Conclusions:
- Demonstrated the feasibility of structure-guided small-molecule discovery targeting the FZD7 TMD.
- Provides a foundation for developing novel FZD modulators for therapeutic applications.
- Highlights the potential of targeting TMDs for Wnt signaling pathway modulation.
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