title: Structure-based design of a benzodiazepine scaffold yields a potent allosteric inhibitor of hepatitis C NS5B RNA polymerase.
abstract: HCV NS5B polymerase, an essential and virus-specific enzyme, is an important target for drug discovery. Using structure-based design, we optimized a 1,5-benzodiazepine NS5B polymerase inhibitor chemotype into a new sulfone-containing scaffold. The design yielded potent inhibitor (S)-4c (K(D) = 0.79 nM), which has approximately 20-fold greater affinity for NS5B than its carbonyl analogue (R)-2c.
authors.affiliation: Tibotec BVBA, Generaal de Wittelaan L 11B 3, B-2800 Mechelen, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Vandyck
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Origène
authors.initials: O
authors.lastname: Nyanguile
authors.forename: Carlo W
authors.initials: CW
authors.lastname: Boutton
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vendeville
authors.forename: David
authors.initials: D
authors.lastname: McGowan
authors.forename: Benoit
authors.initials: B
authors.lastname: Devogelaere
authors.forename: Katie
authors.initials: K
authors.lastname: Amssoms
authors.forename: Stefaan
authors.initials: S
authors.lastname: Last
authors.forename: Klara
authors.initials: K
authors.lastname: Rombauts
authors.forename: Abdellah
authors.initials: A
authors.lastname: Tahri
authors.forename: Pedro
authors.initials: P
authors.lastname: Lory
authors.forename: Lili
authors.initials: L
authors.lastname: Hu
authors.forename: Derek A
authors.initials: DA
authors.lastname: Beauchamp
authors.forename: Kenny
authors.initials: K
authors.lastname: Simmen
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology*; D008958:Models, Molecular; D008968:Molecular Conformation; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; D001569:Benzodiazepines; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase