Structure-based drug design and structural biology study of novel nonpeptide inhibitors of severe acute respiratory syndrome coronavirus main protease

J Med Chem. 2006 Aug 24;49(17):5154-61. doi: 10.1021/jm060207o.


Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (M(pro)), a protein required for the maturation of SARS-CoV, is vital for its life cycle, making it an attractive target for structure-based drug design of anti-SARS drugs. The structure-based virtual screening of a chemical database containing 58,855 compounds followed by the testing of potential compounds for SARS-CoV M(pro) inhibition leads to two hit compounds. The core structures of these two hits, defined by the docking study, are used for further analogue search. Twenty-one analogues derived from these two hits exhibited IC50 values below 50 microM, with the most potent one showing 0.3 microM. Furthermore, the complex structures of two potent inhibitors with SARS-CoV M(pro) were solved by X-ray crystallography. They bind to the protein in a distinct manner compared to all published SARS-CoV M(pro) complex structures. They inhibit SARS-CoV M(pro) activity via intensive H-bond network and hydrophobic interactions, without the formation of a covalent bond. Interestingly, the most potent inhibitor induces protein conformational changes, and the inhibition mechanisms, particularly the disruption of catalytic dyad (His41 and Cys145), are elaborated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Computer Simulation*
  • Coronavirus 3C Proteases
  • Crystallography, X-Ray
  • Cysteine Endopeptidases / isolation & purification
  • Databases, Factual
  • Drug Design*
  • Hydrogen Bonding / drug effects
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Protein Conformation / drug effects
  • Protein Structure, Tertiary
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Severe acute respiratory syndrome-related coronavirus / enzymology*
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis
  • Sulfones / chemistry
  • Sulfones / pharmacology*
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / isolation & purification


  • 2-(((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)thio)-4,5-dihydro-1H-imidazole
  • 6-methoxy-3-nitro-2-(phenylsulfonyl)pyridine
  • Imidazoles
  • Oxadiazoles
  • Protease Inhibitors
  • Pyridines
  • Sulfones
  • Viral Proteins
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases