{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:35:15Z","timestamp":1790771715145,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T00:00:00Z","timestamp":1755475200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T00:00:00Z","timestamp":1755475200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/X001032\/1"],"award-info":[{"award-number":["BB\/X001032\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Angiotensin I\u2010converting enzyme (ACE) is a dipeptidyl carboxypeptidase with two homologous catalytic domains [N\u2010 and C\u2010domains (nACE and cACE)] that can cleave a range of substrates. cACE primarily cleaves the inactive decapeptide angiotensin I into the potent vasopressor angiotensin II, whereas nACE preferentially cleaves the antifibrotic tetrapeptide\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetyl\u2010seryl\u2010aspartyl\u2010lysyl\u2010proline (Ac\u2010SDKP). Several ACE inhibitors, which bind to both cACE and nACE active sites, are used clinically for the treatment of hypertension; however, serious side effects are seen in ~\u200920\u201325% of patients due to nonselective inhibition. To improve ACE inhibitor side effect profiles, the design and development of selective inhibitors of cACE or nACE is desirable for the treatment of hypertension or fibrosis. The detailed molecular basis through which the clinically available ACE inhibitors bind and inhibit cACE and nACE was unknown. Thus, in this study, we have characterised the structural and kinetic basis for the interaction between cACE and nACE with enalaprilat, ramiprilat, trandolaprilat, quinaprilat and perindoprilat. The inhibitors display nanomolar inhibition of both domains, with moderate\u2010to\u2010low cACE\u2010selectivity. Trandolaprilat possesses the highest affinity for both nACE and cACE, whereas quinaprilat displayed the largest cACE\u2010selectivity. None of the binding modes of the inhibitors extend beyond the S1\u2013S2\u2032 subsites to make use of the unique nACE\/cACE residues that have been shown to influence domain selectivity. These findings supplement our understanding of ACE inhibition by the clinically used ACE inhibitors, and this information should be useful in the future design of more domain\u2010selective inhibitors for the treatment of hypertension and cardiovascular diseases.\n                  <\/jats:p>","DOI":"10.1111\/febs.70232","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T17:25:50Z","timestamp":1755537950000},"page":"475-491","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Molecular basis of domain\u2010specific angiotensin I\u2010converting enzyme inhibition by the antihypertensive drugs enalaprilat, ramiprilat, trandolaprilat, quinaprilat and perindoprilat"],"prefix":"10.1111","volume":"293","author":[{"given":"Kyle S.","family":"Gregory","sequence":"first","affiliation":[{"name":"Department of Life Sciences University of Bath  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinasha","family":"Ramasamy","sequence":"additional","affiliation":[{"name":"Department of Integrative Biomedical Sciences, and Institute of Infectious Disease and Molecular Medicine University of Cape Town  South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward D.","family":"Sturrock","sequence":"additional","affiliation":[{"name":"Department of Integrative Biomedical Sciences, and Institute of Infectious Disease and Molecular Medicine University of Cape Town  South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3009-4058","authenticated-orcid":false,"given":"K. 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