Identification of Small-Molecule Compounds Targeting the Dishevelled PDZ Domain by Virtual Screening and Binding Studies

Publication date: Available online 16 March 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Jiwon Choi, SongLing Ma, Hyun-Yi Kim, Ji-Hye Yun, Jung-Nyoung Heo, Weontae Lee, Kang-Yell Choi, Kyoung Tai No
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 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.

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