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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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Novel ketomethylene inhibitors of angiotensin I-converting enzyme (ACE): inhibition and molecular modelling

Pierre Redelinghuys1 / Aloysius T. Nchinda2 / Kelly Chibale3 / Edward D. Sturrock4

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Corresponding author

Citation Information: Biological Chemistry. Volume 387, Issue 4, Pages 461–466, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2006.061, April 2006

Publication History

Received:
August 26, 2005
Accepted:
January 11, 2006
Published Online:
2006-04-11

Abstract

Inhibition of angiotensin I-converting enzyme (ACE) has become an effective strategy in the treatment of hypertension and cardiovascular disease. Keto-ACE, a previously described C-domain selective ACE inhibitor, was used as the basis for the design, synthesis and molecular modelling of a series of novel ketomethylene derivatives for which ACE inhibition profiles and structural characterisation are reported. K i determinations indicated that the introduction of a bulky aromatic tryptophan at the P2′ position of keto-ACE significantly increased selectivity for the C-domain, while an aliphatic P2 Boc group conferred N-domain selectivity. These data were supported by the potential energies of the compounds docked with the C- and N-domains of ACE.

Keywords: kinetics; molecular modelling; physico-chemical characterisation; protease

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