title: Thiazolone-acylsulfonamides as novel HCV NS5B polymerase allosteric inhibitors: convergence of structure-based drug design and X-ray crystallographic study.
abstract: A novel series of thiazolone-acylsulfonamides were designed as HCV NS5B polymerase allosteric inhibitors. The structure based drug designs (SBDD) were guided by docking results that revealed the potential to explore an additional pocket in the allosteric site. In particular, the designed molecules contain moieties of previously described thiazolone and a newly designed acylsulfonamide linker that is in turn connected with a substituted aromatic ring. The selected compounds were synthesized and demonstrated low muM activity. The X-ray complex structure was determined at a 2.2A resolution and converged with the SBDD principle.
authors.affiliation: Valeant Pharmaceutical Research & Development, 3300 Hyland Ave., Costa Mesa, CA 92626, USA. yshunqi@yahoo.com
authors.forename: Shunqi
authors.initials: S
authors.lastname: Yan
authors.forename: Todd
authors.initials: T
authors.lastname: Appleby
authors.forename: Gary
authors.initials: G
authors.lastname: Larson
authors.forename: Jim Z
authors.initials: JZ
authors.lastname: Wu
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hamatake
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
authors.forename: Nanhua
authors.initials: N
authors.lastname: Yao
mesh_terms: D000495:Allosteric Site; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013696:Temperature; D013844:Thiazoles / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000737:chemistry*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D004791:Enzyme Inhibitors; D013449:Sulfonamides; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase