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, Weontae Lee, Kang Yell Choi, Kyoung Tai No

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


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
Issue number15
Publication statusPublished - 2016

Bibliographical note

Funding Information:
This work was supported by the Ministry of Knowledge Economy through Korea Research Institute of Chemical Technology (SI-1205, SI-1304, SI-1404), Translational Research Center for Protein Function Control (2009-0083522) and the Mid-career Researcher Program (NRF-2013R1A2A2A01068963 to WL) from the Ministry of Future Creation and Science (MFCS) of Korea.

Publisher Copyright:
© 2016 Elsevier Ltd

All Science Journal Classification (ASJC) codes

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


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