Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease

J Med Chem. 2009 Aug 27;52(16):5228-40. doi: 10.1021/jm900611t.


We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC(50) = 0.46 microM; antiviral EC(50) = 6 microM). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC(50) = 1.3 microM) and the most potent SARS antiviral activity (EC(50) = 5.2 microM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Chlorocebus aethiops
  • Coronavirus 3C Proteases
  • Crystallography, X-Ray
  • Cysteine Endopeptidases
  • Drug Design
  • Models, Molecular
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Quantitative Structure-Activity Relationship
  • Severe acute respiratory syndrome-related coronavirus / drug effects*
  • Severe acute respiratory syndrome-related coronavirus / enzymology
  • Vero Cells
  • Viral Proteins / antagonists & inhibitors*


  • Antiviral Agents
  • Benzamides
  • N-methyl-5-methylamino-2-methyl-N-((R)-1-(1-naphthyl)ethy)benzamide
  • Naphthalenes
  • Protease Inhibitors
  • Viral Proteins
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases