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-

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• 作者：Andrew J. Prongay ; Zhuyan Guo ; Nanhua Yao ; John Pichardo ; Thierry Fischmann ; Corey Strickland ; Joseph Myers ; Jr. ; Patricia C. Weber ; Brian M. Beyer ; Richard Ingram ; Zhi Hong ; Winifred W. Prosise ; Lata
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：May 17, 2007
• 年：2007
• 卷：50
• 期：10
• 页码：2310 - 2318
• 全文大小：494K
• 年卷期：v.50,no.10(May 17, 2007)
• ISSN：1520-4804

文摘

The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determinedfor a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency werecorrelated with changes in the buried surface area upon binding the inhibitor to the active site. The largestcontribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups asthey 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 potencywith increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of theHCV NS3/4A protease that is currently in clinical trials.