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Discovery of a small-molecule inhibitor of Dvl-CXXC5 interaction by computational approaches

Songling Ma1,2, Jiwon Choi2, Xuemei Jin1

  • 1Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.

Journal of Computer-Aided Molecular Design
|April 9, 2018
PubMed

Insights

Researchers identified a potent inhibitor, BMD4722, that disrupts the CXXC5-Dishevelled (Dvl) interaction. This discovery offers a promising new avenue for developing anabolic therapies to treat osteoporosis by targeting bone formation pathways.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • The Wnt/β-catenin signaling pathway is crucial for osteoblastogenesis and bone formation.
  • CXXC finger protein 5 (CXXC5) negatively regulates osteoblast differentiation by interacting with Dishevelled (Dvl).
  • Targeting the Dvl-CXXC5 interaction presents a potential anabolic therapeutic strategy for osteoporosis.

Purpose of the Study:

  • To simulate the Dvl PDZ domain-CXXC5 peptide complex structure using molecular dynamics.
  • To generate pharmacophore models and perform virtual screening to identify inhibitors of the Dvl-CXXC5 interaction.
  • To discover novel compounds for the anabolic therapy of osteoporosis.

Main Methods:

  • Molecular dynamics (MD) simulations of the Dvl PDZ domain-CXXC5 peptide complex.
  • Generation of pharmacophore models based on structural analysis.
  • Pharmacophore-based virtual screening to identify potential inhibitors.
  • Fluorescence polarization assays, fluorescence spectroscopy, and nuclear magnetic resonance for validation.

Main Results:

  • Four compounds were identified that effectively disrupted the Dvl-CXXC5 interaction.
  • The potent inhibitor BMD4722 was identified, which directly binds to the Dvl PDZ domain.
  • BMD4722 successfully disrupts the Dvl-CXXC5 interaction, validating the computational approach.

Conclusions:

  • A CXXC5-Dvl PDZ domain complex-based pharmacophore approach is effective for developing modulators.
  • The identified inhibitor BMD4722 serves as a promising starting point for designing more potent and specific Dvl-CXXC5 interaction disruptors.
  • This strategy holds potential for the anabolic therapy of osteoporosis.
Keywords:
Dvl–CXXC5 interactionMolecular dynamics simulationNuclear magnetic resonancePharmacophoreVirtual screeningWnt/β-catenin signaling pathway

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