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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography	Molecular basis for multiple omapatrilat binding sites within the ACE C-domain – implications for drug design Gyles E. Cozier , Lauren B. Arendse , Sylva L. Schwager , Edward D. Sturrock , K. Ravi Acharya Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b01309 Diamond Proposal Number(s): [12342] Show Abstract ▼ 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.	Oct 2018

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I03-Macromolecular Crystallography

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

Gyles E. Cozier , Lauren B. Arendse , Sylva L. Schwager , Edward D. Sturrock , K. Ravi Acharya

Journal Of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.8b01309

Diamond Proposal Number(s): [12342]

Show Abstract ▼

Oct 2018