Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: design, synthesis, biological evaluation, and docking studies

Eur J Med Chem. 2013 Oct;68:372-84. doi: 10.1016/j.ejmech.2013.07.037. Epub 2013 Aug 9.


We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki=0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.

Keywords: Cysteine protease inhibitors; Dipeptide; Peptidomimetics; SARS; SARS-CoV 3CL(pro).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Coronavirus 3C Proteases
  • Cysteine Endopeptidases / metabolism
  • Drug Design*
  • Enzyme Activation / drug effects
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Protease Inhibitors* / chemical synthesis
  • Protease Inhibitors* / chemistry
  • Protease Inhibitors* / pharmacology
  • SARS Virus / enzymology*
  • Structure-Activity Relationship
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / metabolism


  • Protease Inhibitors
  • Viral Proteins
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases