Virtual screening identification of novel severe acute respiratory syndrome 3C-like protease inhibitors and in vitro confirmation

Abstract

The 3C-like protease (3CLpro) of severe acute respiratory syndrome associated coronavirus (SARS-CoV) is vital for SARS-CoV replication and is a promising drug target. Structure based virtual screening of 308307 chemical compounds was performed using the computation tool Autodock 3.0.5 on a WISDOM Production Environment. The top 1468 ranked compounds with free binding energy ranging from -14.0 to -17.09kcalmol-1 were selected to check the hydrogen bond interaction with amino acid residues in the active site of 3CLpro. Fifty-three compounds from 35 main groups were tested in an in vitro assay for inhibition of 3CLpro expressed by Escherichia coli. Seven of the 53 compounds were selected. their IC50 ranged from 38.57+/-2.41 to 101.38+/-3.27μM. Two strong 3CLpro inhibitors were further identified as competitive inhibitors of 3CLpro with Ki values of 9.11+/-1.6 and 9.93+/-0.44μM. Hydrophobic and hydrogen bond interactions of compound with amino acid residues in the active site of 3CLpro were also identified.