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- W2018141807 abstract "Despite the similarities in their mechanism of action, the structural requirements for selective interaction with angiotensin-converting enzyme or enkephalinase are different. Inhibitory potency of a series of new mercaptoal-kanoyl amino acids were determined on pure angiotensin-converting enzyme (EC 3.4.15.1) from porcine plasma and on neutral metalloendopeptidase (EC 3.4.24.11) purified from rat brain. This latter enzyme, first designated as enkephalinase, seems to be synaptically involved in the degradation of enkephalins. All tested compounds, whose design was based on the classical active-site model of metallopeptidases, are reversible and competitive inhibitors of both enzymes. Owing to the remarkable similarity in the general topology of metallopeptidases, the differences in optimal binding requirements to enkephalinase and angiotensin-converting enzyme were interpreted from crystallographic studies on related enzymes such as thermolysin and carboxypeptidase A. The large size of the S1′ subsite of enkephalinase allows efficient binding (Ki∼ 2–30 nM) of aromatic and bulky hydrophobic residues such as a cyclohexyl ring. In contrast, a methyl group in position P1′ favors inhibitory potency against angiotensin-converting enzyme while a cyclohexyl ring leads to a complete loss of activity. This feature could mean that optimal binding of the Zn atom present in the catalytic site is a more stringent requirement in angiotensin-converting enzyme than in enkephalinase. An increase in the size of the P1′ component of thiol inhibitors potentiates the affinity for angiotensin-converting enzyme without a significant change on enkephalinase. Finally, methylation of the ultimate amide bond of inhibitors produces a 30-fold decrease in potency towards enkephalinase but does not affect the binding of angiotensin-converting enzyme. These findings allow a rational design of selective inhibitors of enkephalinase, an essential prerequisite for their possible clinical use as new analgesic and psycho-active agents." @default.
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- W2018141807 date "1984-03-01" @default.
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- W2018141807 title "Differences in the structural requirements for selective interaction with neutral metalloendopeptidase (enkephalinase) or angiotensin-converting enzyme. Molecular investigation by use of new thiol inhibitors" @default.
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- W2018141807 doi "https://doi.org/10.1111/j.1432-1033.1984.tb08003.x" @default.
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