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Molecular basis for multiple omapatrilat binding sites within the ACE C-domain – implications for drug design

DOI: 10.1021/acs.jmedchem.8b01309 DOI Help

Authors: Gyles E. Cozier (University of Bath) , Lauren B. Arendse (University of Cape Town) , Sylva L. Schwager (University of Cape Town) , Edward D. Sturrock (University of Cape Town) , K. Ravi Acharya (University of Bath)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: October 2018
Diamond Proposal Number(s): 12342

Abstract: Omapatrilat was designed as a vasopeptidase inhibitor with dual activity against the zinc metallopeptidases angiotensin-1 converting enzyme (ACE) and neprilysin (NEP). ACE has two homologous catalytic domains (nACE and cACE) which exhibit different substrate specificities. Here we report high-resolution crystal structures of omapatrilat in complex with nACE and cACE, and show omapatrilat has sub-nanomolar affinity for both domains. The structures show nearly identical binding interactions for omapatrilat in each domain, explaining the lack of domain selectivity. The cACE complex structure revealed an omapatrilat dimer occupying the cavity beyond the S2 subsite, and this dimer had low micromolar inhibition of nACE and cACE. These results highlight residues beyond the S2 subsite that could be exploited for domain selective inhibition. In addition, it suggests the possibility of either domain specific allosteric inhibitors that bind exclusively to the non-prime cavity, or the potential for targeting specific substrates rather than completely inhibiting the enzyme.

Journal Keywords: Omapatrilat; angiotensin-1 converting enzyme; domain specificity; neutral endopeptidase; crystallography; enzyme kinetics; enzyme structure; metalloprotease

Diamond Keywords: Enzymes

Subject Areas: Chemistry, Medicine, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Added On: 01/11/2018 14:28

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)