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J Synchrotron Radiat. 2008 May;15(Pt 3):204-7. doi: 10.1107/S0909049507064229. Epub 2008 Apr 18.

Key steps in the structure-based optimization of the hepatitis C virus NS3/4A protease inhibitor SCH503034.

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  • 1Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. vincent.madison@spcorp.com

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.

PMID:
18421139
[PubMed - indexed for MEDLINE]
PMCID:
PMC2394794
Free PMC Article
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