title: Non-peptidic small-molecule inhibitors of the single-chain hepatitis C virus NS3 protease/NS4A cofactor complex discovered by structure-based NMR screening.
abstract: NMR-based screening of a customized fragment library identified 16 small-molecule hits that bind weakly (K(D) approximately 100 microM to 10 mM) to substrate binding sites of the NS4A-bound NS3 protease of the hepatitis C virus (HCV). Analogues for five classes of NMR hits were evaluated by a combination of NMR and biochemical data yielding SAR and, in most cases, optimized hits with improved potencies (K(D) approximately K(I) approximately 40 microM to 1 mM). NMR chemical shift perturbation data were used to establish the binding location and orientation of the active site directed scaffolds in these five analogue series. Two of these scaffolds, which bind the enzyme at the proximal S1-S3 and S2' substrate binding sites, were linked together producing competitive inhibitors of the HCV NS3 protease with potencies in the micromolar range. This example illustrates that the low molecular weight scaffolds discovered from structure-based NMR screening can be optimized with focused structure-guided chemistry to produce potent nonpeptidic small-molecule inhibitors of the HCV NS3 protease.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. daniel.wyss@spcorp.com
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Wyss
authors.forename: Ashok
authors.initials: A
authors.lastname: Arasappan
authors.forename: Mary M
authors.initials: MM
authors.lastname: Senior
authors.forename: Yu-Sen
authors.initials: YS
authors.lastname: Wang
authors.forename: Brian M
authors.initials: BM
authors.lastname: Beyer
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
authors.forename: Mark A
authors.initials: MA
authors.lastname: McCoy
mesh_terms: D000813:Anilides / Q000737:chemistry; D001555:Benzene Derivatives / Q000737:chemistry; D001665:Binding Sites; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D016174:Hepacivirus / Q000737:chemistry*; D007211:Indoles / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000813:Anilides; D001555:Benzene Derivatives; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus