title: NMR line-broadening and transferred NOESY as a medicinal chemistry tool for studying inhibitors of the hepatitis C virus NS3 protease domain.
abstract: This work describes the use of NMR as a medicinal chemistry tool for better understanding the binding characteristics of inhibitors of the HCV NS3 protease. The protease-bound structure of a tetrapeptide-like inhibitor that has an acid C-terminus, a norvaline at P1 and a naphthylmethoxy proline at P2 is described. Conformational comparisons are made with a similar compound having a 1-amino-cyclopropylcarboxylic acid at P1 and with a hexapeptide inhibitor. Differences between the free and bound states are identified. 19F NMR also helped in determining that a single complex is observed when an inhibitor is added to the protease at a 1:1 ratio.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim, Laval, Québec, Canada. slaplante@lav.boehringer-ingelheim.com
authors.forename: S R
authors.initials: SR
authors.lastname: LaPlante
authors.forename: N
authors.initials: N
authors.lastname: Aubry
authors.forename: P R
authors.initials: PR
authors.lastname: Bonneau
authors.forename: G
authors.initials: G
authors.lastname: Kukolj
authors.forename: D
authors.initials: D
authors.lastname: Lamarre
authors.forename: S
authors.initials: S
authors.lastname: Lefebvre
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Llinàs-Brunet
authors.forename: C
authors.initials: C
authors.lastname: Plouffe
authors.forename: D R
authors.initials: DR
authors.lastname: Cameron
mesh_terms: D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D009842:Oligopeptides; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus