The Design and Development of a Potent and Selective Novel Diprolyl Derivative That Binds to the N-Domain of Angiotensin-I Converting Enzyme

Stephen Fienberg, Gyles E Cozier, K Ravi Acharya, Kelly Chibale, Edward D Sturrock

Research output: Contribution to journalArticle

Abstract

Angiotensin-I converting enzyme (ACE) is a zinc metalloprotease consisting of two catalytic domains (N- and C-). Most clinical ACE inhibitor(s) (ACEi) have been shown to inhibit both domains nonselectively, resulting in adverse effects such as cough and angioedema. Selectively inhibiting the individual domains is likely to reduce these effects and potentially treat fibrosis in addition to hypertension. ACEi from the GVK Biosciences database were inspected for possible N-domain selective binding patterns. From this set, a diprolyl chemical series was modeled using docking simulations. The series was expanded based on key target interactions involving residues known to impart N-domain selectivity. In total, seven diprolyl compounds were synthesized and tested for N-domain selective ACE inhibition. One compound with an aspartic acid in the P2 position (compound 16) displayed potent inhibition (Ki = 11.45 nM) and was 84-fold more selective toward the N-domain. A high-resolution crystal structure of compound 16 in complex with the N-domain revealed the molecular basis for the observed selectivity.

LanguageEnglish
Pages344-359
Number of pages16
JournalJournal of Medicinal Chemistry
Volume61
Issue number1
Early online date5 Dec 2017
DOIs
StatusPublished - 11 Jan 2018

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Peptidyl-Dipeptidase A
Angioedema
Metalloproteases
Angiotensin-Converting Enzyme Inhibitors
Cough
Aspartic Acid
Zinc
Catalytic Domain
Fibrosis
Databases
Hypertension
L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester

Keywords

  • Journal Article

Cite this

The Design and Development of a Potent and Selective Novel Diprolyl Derivative That Binds to the N-Domain of Angiotensin-I Converting Enzyme. / Fienberg, Stephen; Cozier, Gyles E; Acharya, K Ravi; Chibale, Kelly; Sturrock, Edward D.

In: Journal of Medicinal Chemistry, Vol. 61, No. 1, 11.01.2018, p. 344-359.

Research output: Contribution to journalArticle

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AU - Chibale, Kelly

AU - Sturrock, Edward D

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AB - Angiotensin-I converting enzyme (ACE) is a zinc metalloprotease consisting of two catalytic domains (N- and C-). Most clinical ACE inhibitor(s) (ACEi) have been shown to inhibit both domains nonselectively, resulting in adverse effects such as cough and angioedema. Selectively inhibiting the individual domains is likely to reduce these effects and potentially treat fibrosis in addition to hypertension. ACEi from the GVK Biosciences database were inspected for possible N-domain selective binding patterns. From this set, a diprolyl chemical series was modeled using docking simulations. The series was expanded based on key target interactions involving residues known to impart N-domain selectivity. In total, seven diprolyl compounds were synthesized and tested for N-domain selective ACE inhibition. One compound with an aspartic acid in the P2 position (compound 16) displayed potent inhibition (Ki = 11.45 nM) and was 84-fold more selective toward the N-domain. A high-resolution crystal structure of compound 16 in complex with the N-domain revealed the molecular basis for the observed selectivity.

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