In silico docking yields small molecule negative allosteric modulators targeting the core of Frizzled 7.

Area of Science:

• Pharmacology
• Molecular Biology
• Structural Biology

Background:

• Targeting Frizzled (FZD) receptors, crucial for WNT signaling, is therapeutically promising but challenging due to a lack of effective small molecules.
• No validated ligand binding site has been identified for FZD receptors, hindering drug development.

Purpose of the Study:

• To identify and validate a small molecule inhibitor for Frizzled 7 (FZD7), a potential target for intestinal tumors.
• To demonstrate the feasibility of targeting FZD receptors with small molecules.

Main Methods:

• Utilized adapted docking setups and large molecular library docking screens to identify potential compounds.
• Employed pharmacological assays, biosensors, mutagenesis, cryo-electron microscopy, and molecular dynamics simulations for validation.
• Validated the compound binding site within the transmembrane bundle of FZD7.

Main Results:

• Identified compound C407 as a modulator of FZD7.
• Confirmed C407 as a negative allosteric modulator of WNT/β-catenin signaling.
• Validated the binding site of C407 in the core of the FZD7 transmembrane bundle.

Conclusions:

• Provides proof-of-principle for targeting Frizzled receptors with small molecule compounds.
• C407 represents a potential starting point for developing therapeutics targeting FZD-mediated signaling.
• Further optimization and validation are needed for clinical exploration.