Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design.

Gyles Cozier, Lauren B. Arendse, Sylvia L. Schwager, Edward D. Sturrock, K-Ravi Acharya

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 languageEnglish
Pages (from-to)10141-10154
Number of pages14
JournalJournal of Medicinal Chemistry
Volume61
Issue number22
Early online date29 Oct 2018
DOIs
Publication statusPublished - 21 Nov 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design. / Cozier, Gyles; Arendse, Lauren B. ; Schwager, Sylvia L.; Sturrock, Edward D.; Acharya, K-Ravi.

In: Journal of Medicinal Chemistry, Vol. 61, No. 22, 21.11.2018, p. 10141-10154.

Research output: Contribution to journalArticle

Cozier, Gyles ; Arendse, Lauren B. ; Schwager, Sylvia L. ; Sturrock, Edward D. ; Acharya, K-Ravi. / Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 22. pp. 10141-10154.
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