Domain-selective ligand-binding modes and atomic level pharmacophore refinement in angiotensin I converting enzyme (ACE) inhibitors
Φόρτωση...
Ημερομηνία
Συγγραφείς
Tzakos, A. G.
Gerothanassis, I. P.
Τίτλος Εφημερίδας
Περιοδικό ISSN
Τίτλος τόμου
Εκδότης
Wiley-VCH Verlag
Περίληψη
Τύπος
Είδος δημοσίευσης σε συνέδριο
Είδος περιοδικού
peer reviewed
Είδος εκπαιδευτικού υλικού
Όνομα συνεδρίου
Όνομα περιοδικού
Chembiochem
Όνομα βιβλίου
Σειρά βιβλίου
Έκδοση βιβλίου
Συμπληρωματικός/δευτερεύων τίτλος
Περιγραφή
Somatic 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.
Περιγραφή
Λέξεις-κλειδιά
angiotensin i converting enzyme, drug design, inhibitors, metalloproteins, molecular modeling, molecular recognition, 2 active-sites, aspartyl-lysyl-proline, homologous domains, crystal-structure, protein models, kininase-ii, drug design, c-domain, peptide, substrate
Θεματική κατηγορία
Παραπομπή
Σύνδεσμος
<Go to ISI>://000229730000022
http://onlinelibrary.wiley.com/store/10.1002/cbic.200400386/asset/1089_ftp.pdf?v=1&t=hmn3j195&s=058c7a6aeb4696e93e6c7259dbd8414fed7d6e3a
http://onlinelibrary.wiley.com/store/10.1002/cbic.200400386/asset/1089_ftp.pdf?v=1&t=hmn3j195&s=058c7a6aeb4696e93e6c7259dbd8414fed7d6e3a
Γλώσσα
en
Εκδίδον τμήμα/τομέας
Όνομα επιβλέποντος
Εξεταστική επιτροπή
Γενική Περιγραφή / Σχόλια
Ίδρυμα και Σχολή/Τμήμα του υποβάλλοντος
Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείας