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

Songling Ma, Jiwon Choi, Xuemei Jin, Hyun Yi Kim, Ji Hye Yun, Weontae Lee, Kang Yell Choi, Kyoung Tai No

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


The Wnt/β-catenin signaling pathway plays a significant role in the control of osteoblastogenesis and bone formation. CXXC finger protein 5 (CXXC5) has been recently identified as a negative feedback regulator of osteoblast differentiation through a specific interaction with Dishevelled (Dvl) protein. It was reported that targeting the Dvl–CXXC5 interaction could be a novel anabolic therapeutic target for osteoporosis. In this study, complex structure of Dvl PDZ domain and CXXC5 peptide was simulated with molecular dynamics (MD). Based on the structural analysis of binding modes of MD-simulated Dvl PDZ domain with CXXC5 peptide and crystal Dvl PDZ domain with synthetic peptide–ligands, we generated two different pharmacophore models and applied pharmacophore-based virtual screening to discover potent inhibitors of the Dvl–CXXC5 interaction for the anabolic therapy of osteoporosis. Analysis of 16 compounds selected by means of a virtual screening protocol yielded four compounds that effectively disrupted the Dvl–CXXC5 interaction in the fluorescence polarization assay. Potential compounds were validated by fluorescence spectroscopy and nuclear magnetic resonance. We successfully identified a highly potent inhibitor, BMD4722, which directly binds to the Dvl PDZ domain and disrupts the Dvl–CXXC5 interaction. Overall, CXXC5–Dvl PDZ domain complex based pharmacophore combined with various traditional and simple computational methods is a promising approach for the development of modulators targeting the Dvl–CXXC5 interaction, and the potent inhibitor BMD4722 could serve as a starting point to discover or design more potent and specific the Dvl–CXXC5 interaction disruptors.

Original languageEnglish
Pages (from-to)643-655
Number of pages13
JournalJournal of Computer-Aided Molecular Design
Issue number5
Publication statusPublished - 2018 May 1

Bibliographical note

Funding Information:
Acknowledgements This work was supported by the Ministry of Knowledge Economy through Korea Research Institute of Chemical Dvl PDZ–BMD4722 (black line) complexes obtained from the MD simulations during 50 ns explicit solvent simulations. d Simulated protein–ligand interaction plot of Dvl PDZ domain and BMD4722. Stacked bar charts are normalized over the course of the trajectory, showing the percentages of four type interactions, hydrogen bonds, hydrophobic contacts, ionic interactions and water bridges Technology (SI-1205, SI-1304, SI-1404), and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1A6A3A04010213).

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

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