Identification of small-molecule compounds targeting the dishevelled PDZ domain by virtual screening and binding studies.
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.
Bioinformatics and Molecular Design Research Center, Seoul 120-749, Republic of Korea.
Jiwon
J
Choi
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
SongLing
S
Ma
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.
Hyun-Yi
HY
Kim
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Ji-Hye
JH
Yun
Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
Jung-Nyoung
JN
Heo
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Weontae
W
Lee
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.
Kang-Yell
KY
Choi
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.
Kyoung Tai
KT
No
D000072261:Dishevelled Proteins / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008956:Models, Chemical; D008958:Models, Molecular; D058990:Molecular Targeted Therapy / Q000379:methods; D054731:PDZ Domains; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence / Q000379:methods; D060449:Wnt Signaling Pathway
D000072261:Dishevelled Proteins; D054852:Small Molecule Libraries
Dishevelled; Docking; Fluorescence spectroscopy; PDZ domain; Pharmacophore; Surface plasmon resonance; Virtual screening; Wnt