| Title |
Discovery of a small-molecule inhibitor of Dvl–CXXC5 interaction by computational approaches
|
|---|---|
| Published in |
Perspectives in Drug Discovery and Design, April 2018
|
| DOI | 10.1007/s10822-018-0118-x |
| Pubmed ID | |
| Authors |
Songling Ma, Jiwon Choi, Xuemei Jin, Hyun-Yi Kim, Ji-Hye Yun, Weontae Lee, Kang-Yell Choi, Kyoung Tai No |
| Abstract |
The Wnt/β-catenin signaling pathway plays a significant role in the control of osteoblastogenesis and bone formation. CXXC finger protein 5 (CXXC5) has been recently identified as a negative feedback regulator of osteoblast differentiation through a specific interaction with Dishevelled (Dvl) protein. It was reported that targeting the Dvl-CXXC5 interaction could be a novel anabolic therapeutic target for osteoporosis. In this study, complex structure of Dvl PDZ domain and CXXC5 peptide was simulated with molecular dynamics (MD). Based on the structural analysis of binding modes of MD-simulated Dvl PDZ domain with CXXC5 peptide and crystal Dvl PDZ domain with synthetic peptide-ligands, we generated two different pharmacophore models and applied pharmacophore-based virtual screening to discover potent inhibitors of the Dvl-CXXC5 interaction for the anabolic therapy of osteoporosis. Analysis of 16 compounds selected by means of a virtual screening protocol yielded four compounds that effectively disrupted the Dvl-CXXC5 interaction in the fluorescence polarization assay. Potential compounds were validated by fluorescence spectroscopy and nuclear magnetic resonance. We successfully identified a highly potent inhibitor, BMD4722, which directly binds to the Dvl PDZ domain and disrupts the Dvl-CXXC5 interaction. Overall, CXXC5-Dvl PDZ domain complex based pharmacophore combined with various traditional and simple computational methods is a promising approach for the development of modulators targeting the Dvl-CXXC5 interaction, and the potent inhibitor BMD4722 could serve as a starting point to discover or design more potent and specific the Dvl-CXXC5 interaction disruptors. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 2 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 23 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 23 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 6 | 26% |
| Student > Doctoral Student | 3 | 13% |
| Student > Ph. D. Student | 3 | 13% |
| Professor | 2 | 9% |
| Student > Master | 2 | 9% |
| Other | 2 | 9% |
| Unknown | 5 | 22% |
| Readers by discipline | Count | As % |
|---|---|---|
| Chemistry | 8 | 35% |
| Medicine and Dentistry | 3 | 13% |
| Biochemistry, Genetics and Molecular Biology | 2 | 9% |
| Pharmacology, Toxicology and Pharmaceutical Science | 2 | 9% |
| Immunology and Microbiology | 1 | 4% |
| Other | 3 | 13% |
| Unknown | 4 | 17% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 09 April 2018.
All research outputs
#20,014,336
of 25,461,852 outputs
Outputs from Perspectives in Drug Discovery and Design
#807
of 949 outputs
Outputs of similar age
#252,371
of 343,540 outputs
Outputs of similar age from Perspectives in Drug Discovery and Design
#3
of 5 outputs
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