Virtual Screening of Novel Noncovalent Inhibitors for SARS-CoV 3C-like Proteinase

The SARS coronavirus 3C-like proteinase is considered as a potential drug design target for the treatment of severe acute respiratory syndrome (SARS). Owing to the lack of available drugs for the treatment of SARS, the discovery of inhibitors for SARS coronavirus 3C-like proteinase that can potentia...

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Bibliographic Details
Published in:Journal of chemical information and modeling 2005-01, Vol.45 (1), p.10-17
Main Authors: Liu, Zhenming, Huang, Changkang, Fan, Keqiang, Wei, Ping, Chen, Hao, Liu, Shiyong, Pei, Jianfeng, Shi, Lei, Li, Bo, Yang, Kun, Liu, Ying, Lai, Luhua
Format: Article
Language:English
Subjects:
Binding Sites
Chemical compounds
Computer based modeling
Computer Simulation
Computer-Aided Design
Cysteine Endopeptidases
Drug Design
Endopeptidases - chemistry
Imidazoles - chemistry
Inhibitor drugs
Models, Chemical
Models, Molecular
Molecular Structure
Pharmacology
Protease Inhibitors - chemistry
Severe acute respiratory syndrome
Viral Proteins - antagonists & inhibitors
Viral Proteins - chemistry
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Summary:The SARS coronavirus 3C-like proteinase is considered as a potential drug design target for the treatment of severe acute respiratory syndrome (SARS). Owing to the lack of available drugs for the treatment of SARS, the discovery of inhibitors for SARS coronavirus 3C-like proteinase that can potentially be optimized as drugs appears to be highly desirable. We have built a “flexible” three-dimensional model for SARS 3C-like proteinase by homology modeling and multicanonical molecular dynamics method and used the model for virtual screening of chemical databases. After Dock procedures, strategies including pharmocophore model, consensus scoring, and “drug-like” filters were applied in order to accelerate the process and improve the success rate of virtual docking screening hit lists. Forty compounds were purchased and tested by HPLC and colorimetric assay against SARS 3C-like proteinase. Three of them including calmidazolium, a well-known antagonist of calmodulin, were found to inhibit the enzyme with an apparent K i from 61 to 178 μM. These active compounds and their binding modes provide useful information for understanding the binding sites and for further selective drug design against SARS and other coronavirus.
ISSN:1549-9596
1549-960X
DOI:10.1021/ci049809b