Projects per year
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 subnanomolar 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 nonprime cavity or the potential for targeting specific substrates rather than completely inhibiting the enzyme.
Original language | English |
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Pages (from-to) | 10141-10154 |
Number of pages | 14 |
Journal | Journal of Medicinal Chemistry |
Volume | 61 |
Issue number | 22 |
Early online date | 29 Oct 2018 |
DOIs | |
Publication status | Published - 21 Nov 2018 |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
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Dive into the research topics of 'Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design.'. Together they form a unique fingerprint.Projects
- 2 Finished
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Structure-function Studies on Human Angiotensin-l Concervting Enzyme (Human ACE)
Acharya, R. (PI)
1/02/16 → 30/04/20
Project: Research council
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Structural Studies on Human Angiotensin-1 Converting Enzyme (ACE) and the Design of Novel Domain-Specific Inhibitors
Acharya, R. (PI)
1/10/11 → 30/09/14
Project: Research council