Identification of small-molecule compounds targeting the dishevelled PDZ domain by virtual screening and binding studies

Jiwon Choi, Song Ling Ma, Hyun Yi Kim, Ji Hye Yun, Jung Nyoung Heo, Weon Tae Lee, Kang-Yell Choi, Kyoung Tai No

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The Dishevelled (Dvl) protein, which conveys signals from receptors to the downstream effectors, is a critical constituent of the Wnt/β-catenin signaling pathway. Because the PDZ domain of Dvl protein functions through associations with a wide range of protein partners, Dvl protein involved in the Wnt signaling pathway has been considered to be therapeutic targets in cancers. In this study, we performed structure-based pharmacophore model of the Dvl PDZ domain to discover novel small-molecule binders and identified eight compounds with micromolar affinity. The most potent compound identified, BMD4702, efficiently bound to the Dvl PDZ domain with 11.2 μM affinity and had a 0.186 μM KDvalue according to surface plasmon resonance and fluorescence spectroscopy, respectively. Combining both structural–kinetic relationship analyses and docking studies, we fourmulated that the ligand-binding site is composed of three H-bonds and three hydrophobic features. Thus, our approach led to the identification of potent binders of the Dvl PDZ domain and the findings provide novel insights into structure-based approaches to design high-affinity binders for the Dvl PDZ domain.

Original languageEnglish
Pages (from-to)3259-3266
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number15
DOIs
Publication statusPublished - 2016 Jan 1

Fingerprint

PDZ Domains
Screening
Binders
Molecules
Wnt Signaling Pathway
Proteins
Catenins
Fluorescence spectroscopy
Surface plasmon resonance
Surface Plasmon Resonance
Fluorescence Spectrometry
Binding Sites
Ligands
Dishevelled Proteins
Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

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abstract = "The Dishevelled (Dvl) protein, which conveys signals from receptors to the downstream effectors, is a critical constituent of the Wnt/β-catenin signaling pathway. Because the PDZ domain of Dvl protein functions through associations with a wide range of protein partners, Dvl protein involved in the Wnt signaling pathway has been considered to be therapeutic targets in cancers. In this study, we performed structure-based pharmacophore model of the Dvl PDZ domain to discover novel small-molecule binders and identified eight compounds with micromolar affinity. The most potent compound identified, BMD4702, efficiently bound to the Dvl PDZ domain with 11.2 μM affinity and had a 0.186 μM KDvalue according to surface plasmon resonance and fluorescence spectroscopy, respectively. Combining both structural–kinetic relationship analyses and docking studies, we fourmulated that the ligand-binding site is composed of three H-bonds and three hydrophobic features. Thus, our approach led to the identification of potent binders of the Dvl PDZ domain and the findings provide novel insights into structure-based approaches to design high-affinity binders for the Dvl PDZ domain.",
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Identification of small-molecule compounds targeting the dishevelled PDZ domain by virtual screening and binding studies. / Choi, Jiwon; Ma, Song Ling; Kim, Hyun Yi; Yun, Ji Hye; Heo, Jung Nyoung; Lee, Weon Tae; Choi, Kang-Yell; No, Kyoung Tai.

In: Bioorganic and Medicinal Chemistry, Vol. 24, No. 15, 01.01.2016, p. 3259-3266.

Research output: Contribution to journalArticle

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AU - Heo, Jung Nyoung

AU - Lee, Weon Tae

AU - Choi, Kang-Yell

AU - No, Kyoung Tai

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