Preferred Conformation of Selected ACE Inhibitors for Interactionwith ACE Active Site

Smieško, M. and Remko, M. Preferred Conformation of Selected ACE Inhibitors for Interactionwith ACE Active Site Chemical Papers, Vol.56, No. 2, 2002, 138-143

Document type: Článok z časopisu / Journal Article
Collection: Chemical papers  

Author(s) Smieško, M.
Remko, M.
Title Preferred Conformation of Selected ACE Inhibitors for Interactionwith ACE Active Site
Journal name Chemical Papers
Publication date 2002
Year available 2002
Volume number 56
Issue number 2
ISSN 0366-6352
Start page 138
End page 143
Place of publication Poland
Publisher Versita
Collection year 2002
Language english
Subject 320000 Medical and Health Sciences
320500 Pharmacology and Pharmaceutical Sciences
250000 Chemical Sciences
Abstract/Summary Theoretical methods were used to study structural properties of most common angiotensinconverting enzyme inhibitors (ACEIs): captopril, enalapril, perindopril, ramipril, benazepril, trandolapril, and cilazapril. In the first step, the active metabolites of ACEIs were modeled and all atoms were parametrized by extended MM2 parametrization set. Next, thorough conformational analysis was performed on all rotatable bonds, except those of 3-phenylpropyl or butyl fragment, which were set to low-energy (all-trans) extended arrangement. The values of dihedral angles were varied over the range of 360º in 15º increments and at each step MM2 energy of the rotamer was calculated. Valid low-energy rotamers were saved in a database file; those with intramolecular contact or those with high-energy strain were discarded. Optimal values of dihedral angles were derived from conformational maps and applied to the modeled structure. Several families of low-energy rotamers were identified. For each family, the best representative was chosen and fully optimized with the AM1 method. The lowest-energy conformations were compared to each other and a common pharmacophore was calculated. In addition, structures of ACEIs available in Cambridge Crystallographic Database were taken as a starting point for AM1 geometry optimization. The resulting relaxed structures were compared to those found in conformational search.
 
 
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