NDLI: Optimizing Dvl PDZ domain inhibitor by exploring chemical space

Content Provider	Springer Nature Link
Author	Shan, Jufang Zheng, Jie J.
Copyright Year	2008
Abstract	Because of advances in the high-throughput screening technology, identification of a hit that can bind to a target protein has become a relatively easy task; however, in the process of drug discovery, the following hit-to-lead and lead optimization still remain challenging. In a typical hit-to-lead and lead optimization process, the analogues of the most promising hits are synthesized for the development of structure–activity relationship (SAR) analysis, and in turn, in the effort of optimization of lead compounds, such analysis provides guidance for the further synthesis. The synthesis processes are usually long and labor-intensive. In silico searching has becoming an alternative approach to explore SAR especially with millions of compounds ready to be screened and most of them can be easily obtained. Here, we report our discovery of 15 new Dishevelled PDZ domain inhibitors by using such an approach. In our studies, we first developed a pharmacophore model based on NSC668036, an inhibitor previously identified in our laboratory; based on the model, we then screened the ChemDiv database by using an algorithm that combines similarity search and docking procedures; finally, we selected potent inhibitors based on docking analysis and examined them by using NMR spectroscopy. NMR experiments showed that all the 15 compounds we chose bound to the PDZ domain tighter than NSC668036.
Starting Page	37
Ending Page	47
Page Count	11
File Format	PDF
ISSN	0920654X
Journal	Journal of Computer-Aided Molecular Design
Volume Number	23
Issue Number	1
e-ISSN	15734951
Language	English
Publisher	Springer Netherlands
Publisher Date	2008-09-09
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Chemical space NMR PDZ domain inhibitors SAR Virtual screening Wnt signaling pathway Computer Applications in Chemistry Animal Anatomy / Morphology / Histology Physical Chemistry
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Physical and Theoretical Chemistry Computer Science Applications

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