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 journalArticle

2 Citations (Scopus)

Abstract

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
Volume32
Issue number5
DOIs
Publication statusPublished - 2018 May 1

Fingerprint

PDZ Domains
inhibitors
Proteins
Molecules
Fingers
Peptides
Molecular dynamics
molecules
Molecular Dynamics Simulation
Screening
osteoporosis
proteins
Osteoporosis
interactions
Catenins
Osteoblasts
Fluorescence spectroscopy
Computational methods
peptides
Wnt Signaling Pathway

All Science Journal Classification (ASJC) codes

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

Cite this

Ma, Songling ; Choi, Jiwon ; Jin, Xuemei ; Kim, Hyun Yi ; Yun, Ji Hye ; Lee, Weontae ; Choi, Kang-Yell ; No, Kyoung Tai. / Discovery of a small-molecule inhibitor of Dvl–CXXC5 interaction by computational approaches. In: Journal of Computer-Aided Molecular Design. 2018 ; Vol. 32, No. 5. pp. 643-655.
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abstract = "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.",
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Discovery of a small-molecule inhibitor of Dvl–CXXC5 interaction by computational approaches. / Ma, Songling; Choi, Jiwon; Jin, Xuemei; Kim, Hyun Yi; Yun, Ji Hye; Lee, Weontae; Choi, Kang-Yell; No, Kyoung Tai.

In: Journal of Computer-Aided Molecular Design, Vol. 32, No. 5, 01.05.2018, p. 643-655.

Research output: Contribution to journalArticle

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AU - Ma, Songling

AU - Choi, Jiwon

AU - Jin, Xuemei

AU - Kim, Hyun Yi

AU - Yun, Ji Hye

AU - Lee, Weontae

AU - Choi, Kang-Yell

AU - No, Kyoung Tai

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