title: Key steps in the structure-based optimization of the hepatitis C virus NS3/4A protease inhibitor SCH503034.
abstract: The structures of both native and S139A holo-HCV NS3/4A protease domain were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contributions to the binding energy arise from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease, which is currently in clinical trials.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. vincent.madison@spcorp.com
authors.forename: Vincent
authors.initials: V
authors.lastname: Madison
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Prongay
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.forename: Nanhua
authors.initials: N
authors.lastname: Yao
authors.forename: John
authors.initials: J
authors.lastname: Pichardo
authors.forename: Thierry
authors.initials: T
authors.lastname: Fischmann
authors.forename: Corey
authors.initials: C
authors.lastname: Strickland
authors.forename: Joseph
authors.initials: J
authors.lastname: Myers
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Weber
authors.forename: Brian M
authors.initials: BM
authors.lastname: Beyer
authors.forename: Richard
authors.initials: R
authors.lastname: Ingram
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
authors.forename: Winifred W
authors.initials: WW
authors.lastname: Prosise
authors.forename: Lata
authors.initials: L
authors.lastname: Ramanathan
authors.forename: S Shane
authors.initials: SS
authors.lastname: Taremi
authors.forename: Taisa
authors.initials: T
authors.lastname: Yarosh-Tomaine
authors.forename: Rumin
authors.initials: R
authors.lastname: Zhang
authors.forename: Mary
authors.initials: M
authors.lastname: Senior
authors.forename: Rong Sheng
authors.initials: RS
authors.lastname: Yang
authors.forename: Bruce
authors.initials: B
authors.lastname: Malcolm
authors.forename: Ashok
authors.initials: A
authors.lastname: Arasappan
authors.forename: Frank
authors.initials: F
authors.lastname: Bennett
authors.forename: Stephane L
authors.initials: SL
authors.lastname: Bogen
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.forename: Edwin
authors.initials: E
authors.lastname: Jao
authors.forename: Yi Tsung
authors.initials: YT
authors.lastname: Liu
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Lovey
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saksena
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Viyyoor
authors.initials: V
authors.lastname: Girijavallabhan
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
mesh_terms: D016174:Hepacivirus / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D011392:Proline; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080106:NS4A protein, flavivirus; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide