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) ( IC50 <= 30 mu M), 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) ( IC50 = 3-1000 mu M). These compounds, 28 in total, were subjected to 3D-QSAR studies to elucidate the pharmacophore of SARS-CoV 3CL(pro).