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.

Summary for 3V3M

• Entry DOI: 10.2210/pdb3v3m/pdb
• Descriptor: 3C-like proteinase, N-[(1R)-2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-N-(4-tert-butylphenyl)furan-2-carboxamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: chymotrypsin like fold, viral polypeptide protease, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: SARS coronavirus (SARS-CoV)
• Cellular location: Non-structural protein 3: Host membrane; Multi-pass membrane protein (Potential). Non-structural protein 4: Host membrane; Multi-pass membrane protein (Potential). Non-structural protein 6: Host membrane; Multi-pass membrane protein (Potential). Non-structural protein 7: Host cytoplasm, host perinuclear region (By similarity). Non-structural protein 8: Host cytoplasm, host perinuclear region (By similarity). Non-structural protein 9: Host cytoplasm, host perinuclear region (By similarity). Non-structural protein 10: Host cytoplasm, host perinuclear region (By similarity): P0C6U8
• Total number of polymer chains: 1
• Total formula weight: 34466.45

Authors

Jacobs, J.,Grum-Tokars, V.,Zhou, Y.,Turlington, M.,Saldanha, S.A.,Chase, P.,Eggler, A.,Dawson, E.S.,Baez-Santos, Y.M.,Tomar, S.,Mielech, A.M.,Baker, S.C.,Lindsley, C.W.,Hodder, P.,Mesecar, A.,Stauffer, S.R. (deposition date: 2011-12-13, release date: 2013-01-16, Last modification date: 2024-02-28)

Primary citation

Jacobs, J.,Grum-Tokars, V.,Zhou, Y.,Turlington, M.,Saldanha, S.A.,Chase, P.,Eggler, A.,Dawson, E.S.,Baez-Santos, Y.M.,Tomar, S.,Mielech, A.M.,Baker, S.C.,Lindsley, C.W.,Hodder, P.,Mesecar, A.,Stauffer, S.R.
Discovery, Synthesis, And Structure-Based Optimization of a Series of N-(tert-Butyl)-2-(N-arylamido)-2-(pyridin-3-yl) Acetamides (ML188) as Potent Noncovalent Small Molecule Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease.
J.Med.Chem., 56:534-546, 2013

PubMed Abstract: 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.

PubMed: 23231439
DOI: 10.1021/jm301580n

Experimental method

X-RAY DIFFRACTION (1.96 Å)