Discovery of a novel family of SARS-CoV protease inhibitors by virtual screening and 3D-QSAR studies.
The severe acute respiratory syndrome-associated coronavirus (SARS-CoV) 3C-like protease (3CL(pro) or M(pro)) is an attractive target for the development of anti-SARS drugs because of its crucial role in the viral life cycle. In this study, a compound database was screened by the structure-based virtual screening approach to identify initial hits as inhibitors of SARS-CoV 3CL(pro). Out of the 59,363 compounds docked, 93 were selected for the inhibition assay, and 21 showed inhibition against SARS-CoV 3CL(pro) (IC(50) <or= 30 microM), with three of them having common substructures. Furthermore, a search for analogues with common substructure in the Maybridge, ChemBridge, and SPECS_SC databases led to the identification of another 25 compounds that exhibited inhibition against SARS-CoV 3CL(pro) (IC(50) = 3-1,000 microM). These compounds, 28 in total, were subjected to 3D-QSAR studies to elucidate the pharmacophore of SARS-CoV 3CL(pro).
Tsai
Keng-Chang
KC
Department of Life Science, Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300, Taiwan, Republic of China.
Chen
Shih-Yuan
SY
Liang
Po-Huang
PH
Lu
I-Lin
IL
Mahindroo
Neeraj
N
Hsieh
Hsing-Pang
HP
Chao
Yu-Sheng
YS
Liu
Lincoln
L
Liu
Donald
D
Lien
Wei
W
Lin
Thy-Hou
TH
Wu
Su-Ying
SY
D001665:Binding Sites; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D009842:Oligopeptides; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases