Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization.
The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation 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 contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. 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 that is currently in clinical trials.
Prongay
Andrew J
AJ
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. andrew.prongay@spcorp.com
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
Madison
Vincent
V
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000201:enzymology*; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D011487:Protein Conformation; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D013237:Stereoisomerism; 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
D000998:Antiviral Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011392:Proline; D015842:Serine Proteinase Inhibitors; 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; 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