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

Jiwon Choi; SongLing Ma; Hyun-Yi Kim; Ji-Hye Yun; Jung-Nyoung Heo; Weontae Lee; Kang-Yell Choi; Kyoung Tai No

doi:10.1016/j.bmc.2016.03.026

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

Bioorg Med Chem. 2016 Aug 1;24(15):3259-66. doi: 10.1016/j.bmc.2016.03.026. Epub 2016 Mar 16.

Authors

Jiwon Choi¹, SongLing Ma², Hyun-Yi Kim³, Ji-Hye Yun², Jung-Nyoung Heo⁴, Weontae Lee², Kang-Yell Choi³, Kyoung Tai No⁵

Affiliations

¹ Bioinformatics and Molecular Design Research Center, Seoul 120-749, Republic of Korea.
² Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
³ Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea; Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea.
⁴ Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
⁵ Bioinformatics and Molecular Design Research Center, Seoul 120-749, Republic of Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea. Electronic address: ktno@bmdrc.org.

PMID: 27112452
DOI: 10.1016/j.bmc.2016.03.026

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 11.2μM affinity and had a 0.186μM KD value 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.

Keywords: Dishevelled; Docking; Fluorescence spectroscopy; PDZ domain; Pharmacophore; Surface plasmon resonance; Virtual screening; Wnt.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dishevelled Proteins / chemistry
Dishevelled Proteins / metabolism*
Drug Evaluation, Preclinical / methods*
Models, Chemical*
Models, Molecular
Molecular Targeted Therapy / methods
PDZ Domains
Protein Binding
Small Molecule Libraries / chemistry*
Small Molecule Libraries / pharmacology*
Spectrometry, Fluorescence / methods
Wnt Signaling Pathway

Substances

Dishevelled Proteins
Small Molecule Libraries