Using the Electrostatic Field Effect to Design a New Class of Inhibitors for Cysteine Proteases

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• 作者：Jeffrey L. Conroy ; Tanya C. Sanders ; and Christopher T. Seto
• 刊名：Journal of the American Chemical Society
• 出版年：1997
• 出版时间：May 7, 1997
• 年：1997
• 卷：119
• 期：18
• 页码：4285 - 4291
• 全文大小：225K
• 年卷期：v.119,no.18(May 7, 1997)
• ISSN：1520-5126

文摘

A new class of competitive inhibitors for the cysteineprotease papain is described. These inhibitors arebased upon a 4-heterocyclohexanone ring and are designed to react withthe enzyme active site nucleophile to givea reversibly formed hemithioketal. The electrophilicity of theketone in these inhibitors is enhanced by ring strainand by through-space electrostatic repulsion with the heteroatom at the1-position of the ring. Equilibrium constantsfor addition of water and 3-mercaptopropionic acid to several4-heterocyclohexanones were measured by ¹H NMRspectroscopy. These reactions model addition of the active sitenucleophile to the corresponding inhibitors. Theequilibrium constants give a linear correlation with the fieldsubstituent constant F for the functional group atthe1-position of the heterocyclohexanone. These equilibrium constantsalso correlate well with the inhibition constantsfor the 4-heterocyclohexanone-based inhibitors, which range from 11 to120 M. Thus, the model system can beused to predict the potency of structurally related enzymeinhibitors.