Skip to content
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Fragment-based design for the development of n-domain-selective angiotensin-1-converting enzyme inhibitors
Clinical Science, Volume 126, No. 4, Year 2014
Notification
URL copied to clipboard!
Description
ACE (angiotensin-1-converting enzyme) is a zinc metallopeptidase that plays a prominent role in blood pressure regulation and electrolyte homeostasis. ACE consists of two homologous domains that despite similarities of sequence and topology display differences in substrate processing and inhibitor binding. The design of inhibitors that selectively inhibit the N-domain (N-selective) could be useful in treating conditions of tissue injury and fibrosis due to build-up of N-domain-specific substrate Ac-SDKP (N-acetyl-Ser-Asp-Lys-Pro). Using a receptor-based SHOP (scaffold hopping) approach with N-selective inhibitor RXP407, a shortlist of scaffolds that consisted of modified RXP407 backbones with novel chemotypes was generated. These scaffolds were selected on the basis of enhanced predicted interaction energies with N-domain residues that differed from their C-domain counterparts. One scaffold was synthesized and inhibitory binding tested using a fluorogenic ACE assay. A molecule incorporating a tetrazole moiety in the P2 position (compound 33RE) displayed potent inhibition (Ki =11.21+- 0.74 nM) and was 927-fold more selective for the N-domain than the C-domain. A crystal structure of compound 33RE in complex with the N-domain revealed its mode of binding through aromatic stacking with His388 and a direct hydrogen bond with the hydroxy group of the N-domain specific Tyr369. This work further elucidates the molecular basis for N-domainselective inhibition and assists in the design of novel N-selective ACE inhibitors that could be employed in treatment of fibrosis disorders. © 2014 Biochemical Society.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3875237/bin/cs1260305add.pdf
Authors & Co-Authors
Douglas, Ross G.
South Africa, Cape Town
University of Cape Town
Sharma, Rajni Kant
South Africa, Cape Town
University of Cape Town
Masuyer, Geoffrey
South Africa, Cape Town
University of Cape Town
Lubbe, Lizelle
South Africa, Cape Town
University of Cape Town
Zamora, Ismael
Spain, Barcelona
Universitat Pompeu Fabra Barcelona
Ravi Acharya, K.
United Kingdom, Bath
University of Bath
Chibale, Kelly
South Africa, Cape Town
University of Cape Town
Sturrock, Edward D.
South Africa, Cape Town
University of Cape Town
Statistics
Citations: 32
Authors: 8
Affiliations: 3
Identifiers
Doi:
10.1042/CS20130403
ISSN:
01435221
Research Areas
Noncommunicable Diseases
Violence And Injury