Journal of Computer-Aided Molecular Design

, Volume 32, Issue 5, pp 643–655 | Cite as

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


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.


Wnt/β-catenin signaling pathway Dvl–CXXC5 interaction Pharmacophore Virtual screening Molecular dynamics simulation Nuclear magnetic resonance 



This work was supported by the Ministry of Knowledge Economy through Korea Research Institute of Chemical 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).

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biotechnology, College of Life Science and BiotechnologyYonsei UniversitySeoulRepublic of Korea
  2. 2.Bioinformatics and Molecular Design Research CenterYonsei UniversitySeoulRepublic of Korea
  3. 3.Translational Research Center for Protein Function ControlYonsei UniversitySeoulRepublic of Korea
  4. 4.Department of Biochemistry, College of Life Science and BiotechnologyYonsei UniversitySeoulRepublic of Korea

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