3V3M : Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease in Complex with N-[(1R)-2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-N-(4-tert-butylphenyl)furan-2-carboxamide inhibitor.

  • Sakshi Tomar (Contributor)
  • Andrew D. Mesecar (Contributor)
  • Mark Turlington (Contributor)
  • Aimee Eggler (Contributor)
  • Valerie Grum-Tokars (Contributor)
  • Jon Jacobs (Contributor)
  • Eric S. Dawson (Contributor)
  • Peter Chase (Contributor)
  • Yahira M. Baez-Santos (Contributor)
  • Craig W. Lindsley (Contributor)
  • Peter Hodder (Contributor)
  • Shaun R. Stauffer (Contributor)
  • Ya Zhou (Contributor)
  • S. Adrian Saldanha (Contributor)
  • Anna M. Mielech (Contributor)
  • S. C. Baker (Contributor)



Experimental Technique/Method:X-RAY DIFFRACTION
Release Date:2013-01-16
Deposition Date:2011-12-13
Revision Date:2013-02-13
Molecular Weight:34466.45
Macromolecule Type:Protein
Residue Count:306
Atom Site Count:2452

A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S(1'), S(1), and S(2) enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.
Date made available2013

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