Key steps in the structure-based optimization of the hepatitis C virus NS3/4A protease inhibitor SCH503034.
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.
Madison
Vincent
V
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. vincent.madison@spcorp.com
Prongay
Andrew J
AJ
Guo
Zhuyan
Z
Yao
Nanhua
N
Pichardo
John
J
Fischmann
Thierry
T
Strickland
Corey
C
Myers
Joseph
J
Weber
Patricia C
PC
Beyer
Brian M
BM
Ingram
Richard
R
Hong
Zhi
Z
Prosise
Winifred W
WW
Ramanathan
Lata
L
Taremi
S Shane
SS
Yarosh-Tomaine
Taisa
T
Zhang
Rumin
R
Senior
Mary
M
Yang
Rong Sheng
RS
Malcolm
Bruce
B
Arasappan
Ashok
A
Bennett
Frank
F
Bogen
Stephane L
SL
Chen
Kevin
K
Jao
Edwin
E
Liu
Yi Tsung
YT
Lovey
Raymond G
RG
Saksena
Anil K
AK
Venkatraman
Srikanth
S
Girijavallabhan
Viyyoor
V
Njoroge
F George
FG
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
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