title: Discovering severe acute respiratory syndrome coronavirus 3CL protease inhibitors: virtual screening, surface plasmon resonance, and fluorescence resonance energy transfer assays.
abstract: An integrated system has been developed for discovering potent inhibitors of severe acute respiratory syndrome coronavirus 3C-like protease (SARS-CoV 3CL(pro)) 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 3CL(pro). The enzymatic inhibition activities of these 52 SARS-CoV 3CL(pro) binders were further applied to FRET-based assay, and IC(50) values were determined. Based on this integrated assay platform, 8 new SARS-CoV 3CL(pro) inhibitors were discovered. The fact that the obtained IC(50) values for the inhibitors are in good accordance with the discovered dissociation equilibrium constants (K(D)s) 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 3CL(pro) inhibitors, and the determined inhibitors could be used as possible lead compounds for further research.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Shuai
authors.initials: S
authors.lastname: Chen
authors.forename: Chunshan
authors.initials: C
authors.lastname: Gui
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D001665:Binding Sites; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods*; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D020349:Surface Plasmon Resonance / Q000379:methods*; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases