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Discovering Severe Acute Respiratory Syndrome Coronavirus 3CL Protease Inhibitors: Virtual Screening, Surface Plasmon Resonance, and Fluorescence Resonance Energy Transfer AssaysDrug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China, School of Pharmacy, East China University of Science and Technology, Shanghai, China
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China, School of Pharmacy, East China University of Science and Technology, Shanghai, China An integrated system has been developed for discovering potent inhibitors of severe acute respiratory syndrome coronavirus 3C-like protease (SARS-CoV 3CLpro) by virtual screening correlating with surface plasmon resonance (SPR) and fluorescence resonance energy transfer (FRET) technologies-based assays. The authors screened 81,287 small molecular compounds against SPECS database by virtual screening; 256 compounds were subsequently selected for biological evaluation. Through SPR technology-based assay, 52 from these 256 compounds were discovered to show binding to SARS-CoV 3CLpro. The enzymatic inhibition activities of these 52 SARS-CoV 3CLpro binders were further applied to FRET-based assay, and IC50 values were determined. Based on this integrated assay platform, 8 new SARS-CoV 3CLpro inhibitors were discovered. The fact that the obtained IC50 values for the inhibitors are in good accordance with the discovered dissociation equilibrium constants (KDs) assayed by SPR implied the reliability of this platform. Our current work is hoped to supply a powerful approach in the discovery of potent SARS-CoV 3CLpro inhibitors, and the determined inhibitors could be used as possible lead compounds for further research.
Key Words: SARS • SARS-CoV 3CLpro • inhibitor • virtual screening • SPR • FRET
This version was published on December
1, 2006 Journal of Biomolecular Screening, Vol. 11, No. 8,
915-921 (2006) |
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