Domain-selective ligand-binding modes and atomic level pharmacophore refinement in angiotensin I converting enzyme (ACE) inhibitors (Journal article)

Tzakos, A. G./ Gerothanassis, I. P.

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dc.contributor.authorTzakos, A. G.en
dc.contributor.authorGerothanassis, I. P.en
dc.date.accessioned2015-11-24T16:56:34Z-
dc.date.available2015-11-24T16:56:34Z-
dc.identifier.issn1439-4227-
dc.identifier.urihttps://olympias.lib.uoi.gr/jspui/handle/123456789/10454-
dc.rightsDefault Licence-
dc.subjectangiotensin i converting enzymeen
dc.subjectdrug designen
dc.subjectinhibitorsen
dc.subjectmetalloproteinsen
dc.subjectmolecular modelingen
dc.subjectmolecular recognitionen
dc.subject2 active-sitesen
dc.subjectaspartyl-lysyl-prolineen
dc.subjecthomologous domainsen
dc.subjectcrystal-structureen
dc.subjectprotein modelsen
dc.subjectkininase-iien
dc.subjectdrug designen
dc.subjectc-domainen
dc.subjectpeptideen
dc.subjectsubstrateen
dc.titleDomain-selective ligand-binding modes and atomic level pharmacophore refinement in angiotensin I converting enzyme (ACE) inhibitorsen
heal.typejournalArticle-
heal.type.enJournal articleen
heal.type.elΆρθρο Περιοδικούel
heal.identifier.primaryDOI 10.1002/cbic.200400386-
heal.identifier.secondary<Go to ISI>://000229730000022-
heal.identifier.secondaryhttp://onlinelibrary.wiley.com/store/10.1002/cbic.200400386/asset/1089_ftp.pdf?v=1&t=hmn3j195&s=058c7a6aeb4696e93e6c7259dbd8414fed7d6e3a-
heal.languageen-
heal.accesscampus-
heal.recordProviderΠανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείαςel
heal.publicationDate2005-
heal.abstractSomatic ACE (EC 3.4.15. 1), a Zn-II metalloproteinose, is composed of functionally active N and C domains resulting from tandem gene duplication. Despite the high degree of sequence similarity between the two domains, they differ in substrate and inhibitor specificity and in their activation by chloride ions. Because of the critical role of ACE in cardiovascular and renal diseases, both domains ore attractive targets for drug design. Putative structural models have been generated for the interactions of ACE inhibitors (lisinopril, captoril, enaloprilat, keto-ACE, ramiprilot, quinaprilat, peridoprilat, fosinoprilat, and RXP 407) with both the ACE-C and the ACE_N domains. Inhibitor-domain selectivity was interpreted in terms of residue alterations observed in the four subsites of the binding grooves of the ACE C/ACE N domains (SI: V516/N494, V578/T496, S2: F391/Y369, E403/R381, S1': D377/ Q355, E162/D140, V379/S357, V380/T358, and S2': D463/E431, T282/S260). The interactions governing the ligand-receptor recognition process in the ACE_C domain are: a salt bridge between D377, E162, and the NH2 group (P1' position), a hydrogen bond of the inhibitor with Q281, the presence of bulky hydrophobic groups in the P1 and P2' sites, and a stacking interaction of F391 with a benzyl group in the P2 position. In ACE_N these interactions are: hydrogen bonds of the inhibitor with E431, Y369, and R381, and a salt bridge between the carboxy group in the P2 position of the inhibitor and R500. The calculated complexes were evaluated for their consistency with structure-activity relationships and site-directed mutogenesis data. A comparison between the calculated interaction free energies and the experimentally observed biological activities was also made. Pharmocophore refinement was achieved at an atomic level, and might provide an improved basis for structure-based rational design of second-generation, domoin-selective inhibitors.en
heal.publisherWiley-VCH Verlagen
heal.journalNameChembiochemen
heal.journalTypepeer reviewed-
heal.fullTextAvailabilityTRUE-
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