Development of N-domain selective Angiotensin-I Converting Enzyme (ACE) inhibitors using Computer Aided Drug Discovery (CADD)
type: CreativeWork
description: Angiotensin-I (Ang-I) converting enzyme (ACE) is a zinc metalloprotease that plays a vital role in the Renin Angiotensin Aldosterone System (RAAS) and is a key antihypertensive drug target. In addition to Ang-I, ACE cleaves many other physiological substrates, thus extending its function beyond the regulation of blood pressure. Somatic ACE (sACE) consists of two structurally homologous yet distinct catalytic sites termed the N- and C-domains. The two catalytic domains of ACE have distinct substrate affinities and play different regulatory roles. The antifibrotic tetrapeptide Ac-SDKP is hydrolysed solely by the N-domain and thus is a potential target for interactions between the ligand and unique residues within the active site of the N- and C-domains, which need to be exploited to effect either N- or Cdomain selectivity. N-domain selective ACE inhibition has been demonstrated with peptides while crystallographic studies have shown that the N-domain to C-domain substitution of Arg381 with Glu403 within the S₂ subsite is integral to N-domain selective ACE inhibition. Three computer aided drug discovery (CADD) approaches were pursued to design N-domain selective drug-like ACE inhibitors (ACEi) with an acidic P₂ functional group that would confer N-domain selectivity via an interaction with Arg381 in the S₂ subsite. Firstly, a fragment-based screening protocol was performed by running a set of chemical filters on 16 000 drug fragment compounds (MW < 350), all of which contained a metal chelating group. 60 Ligands capable of binding to both the zinc metal and Arg381 in the S₂ subsite of the N-domain were tested for ACE inhibition against the two domains of ACE. Two of the fragments identified in this screen showed a modest ACE inhibition (IC₅₀ +/- 200 μM), but no domain selectivity. Secondly, a combinatorial library was created to explore the P₂ structure activity relationship (SAR) of a scaffold based on the core structure of the clinical ACEi, Enalaprilat. Over 400 var…
abstract: Angiotensin-I (Ang-I) converting enzyme (ACE) is a zinc metalloprotease that plays a vital role in the Renin Angiotensin Aldosterone System (RAAS) and is a key antihypertensive drug target. In addition to Ang-I, ACE cleaves many other physiological substrates, thus extending its function beyond the regulation of blood pressure. Somatic ACE (sACE) consists of two structurally homologous yet distinct catalytic sites termed the N- and C-domains. The two catalytic domains of ACE have distinct substrate affinities and play different regulatory roles. The antifibrotic tetrapeptide Ac-SDKP is hydrolysed solely by the N-domain and thus is a potential target for interactions between the ligand and unique residues within the active site of the N- and C-domains, which need to be exploited to effect either N- or Cdomain selectivity. N-domain selective ACE inhibition has been demonstrated with peptides while crystallographic studies have shown that the N-domain to C-domain substitution of Arg381 with Glu403 within the S₂ subsite is integral to N-domain selective ACE inhibition. Three computer aided drug discovery (CADD) approaches were pursued to design N-domain selective drug-like ACE inhibitors (ACEi) with an acidic P₂ functional group that would confer N-domain selectivity via an interaction with Arg381 in the S₂ subsite. Firstly, a fragment-based screening protocol was performed by running a set of chemical filters on 16 000 drug fragment compounds (MW < 350), all of which contained a metal chelating group. 60 Ligands capable of binding to both the zinc metal and Arg381 in the S₂ subsite of the N-domain were tested for ACE inhibition against the two domains of ACE. Two of the fragments identified in this screen showed a modest ACE inhibition (IC₅₀ +/- 200 μM), but no domain selectivity. Secondly, a combinatorial library was created to explore the P₂ structure activity relationship (SAR) of a scaffold based on the core structure of the clinical ACEi, Enalaprilat. Over 400 var…
author: Fienberg, Stephen
language: eng
date published: 2017
date modified: 2026-07-22T22:23:14Z
provider: University of Cape Town
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Department of Chemistry

PropertyValue
property ID: Handle
value: http://hdl.handle.net/11427/25656