title: 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.
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.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Jacobs
authors.forename: Valerie
authors.initials: V
authors.lastname: Grum-Tokars
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhou
authors.forename: Mark
authors.initials: M
authors.lastname: Turlington
authors.forename: S Adrian
authors.initials: SA
authors.lastname: Saldanha
authors.forename: Peter
authors.initials: P
authors.lastname: Chase
authors.forename: Aimee
authors.initials: A
authors.lastname: Eggler
authors.forename: Eric S
authors.initials: ES
authors.lastname: Dawson
authors.forename: Yahira M
authors.initials: YM
authors.lastname: Baez-Santos
authors.forename: Sakshi
authors.initials: S
authors.lastname: Tomar
authors.forename: Anna M
authors.initials: AM
authors.lastname: Mielech
authors.forename: Susan C
authors.initials: SC
authors.lastname: Baker
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.forename: Andrew
authors.initials: A
authors.lastname: Mesecar
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D045169:Severe Acute Respiratory Syndrome / Q000821:virology*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D011480:Protease Inhibitors; D054852:Small Molecule Libraries