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

Bioorg Med Chem Lett. 2011 May 15;21(10):3088-91. doi: 10.1016/j.bmcl.2011.03.034. Epub 2011 Mar 16.

Abstract

The 3C-like protease (3CL(pro)) 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 -17.09 kcal mol(-1) were selected to check the hydrogen bond interaction with amino acid residues in the active site of 3CL(pro). Fifty-three compounds from 35 main groups were tested in an in vitro assay for inhibition of 3CL(pro) expressed by Escherichia coli. Seven of the 53 compounds were selected; their IC(50) ranged from 38.57±2.41 to 101.38±3.27 μM. Two strong 3CL(pro) inhibitors were further identified as competitive inhibitors of 3CL(pro) with K(i) values of 9.11±1.6 and 9.93±0.44 μM. Hydrophobic and hydrogen bond interactions of compound with amino acid residues in the active site of 3CL(pro) were also identified.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3C Viral Proteases
  • Binding, Competitive
  • Computer Simulation*
  • Cysteine Endopeptidases / genetics
  • Drug Delivery Systems*
  • Enzyme Activation / drug effects*
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Protease Inhibitors* / chemistry
  • Protease Inhibitors* / pharmacology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • SARS Virus / drug effects*
  • SARS Virus / enzymology
  • Small Molecule Libraries*
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / genetics

Substances

  • Protease Inhibitors
  • Recombinant Proteins
  • Small Molecule Libraries
  • Viral Proteins
  • Cysteine Endopeptidases
  • 3C Viral Proteases
  • 3C proteases