Using the electrostatic field effect to design a new class of inhibitors for cysteine proteases
A new class of competitive inhibitors for the cysteine protease papain is described. These inhibitors are based upon a 4-heterocyclohexanone ring and are designed to react with the enzyme active site nucleophile to give a reversibly formed hemithioketal. The electrophilicity of the ketone in these inhibitors is enhanced by ring strain and by through-space electrostatic repulsion with the heteroatom at the 1-position of the ring. Equilibrium constants for addition of water and 3-mercaptopropionic acid to several 4- heterocyclohexanones were measured by 1H NMR spectroscopy. These reactions model addition of the active site nucleophile to the corresponding inhibitors. The equilibrium constants give a linear correlation with the field substituent constant F for the functional group at the 1-position of the heterocyclohexanone. These equilibrium constants also correlate well with the inhibition constants for the 4-heterocyclohexanone-based inhibitors, which range from 11 to 120 μM. Thus, the model system can be used to predict the potency of structurally related enzyme inhibitors.
Conroy, Jeffrey L.,Sanders, Tanya C.,Seto, Christopher T.
p. 4285 - 4291
(2007/10/03)
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