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.
Bibliographical noteFunding 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.
© 2016 Elsevier Ltd
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry