ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Preferred Conformation of Selected ACE Inhibitors for Interactionwith ACE Active Site

M. Smieško and M. Remko

Department of Pharmaceutical Chemistry, Faculty of Pharmacy,Comenius University, SK-832 32 Bratislava

E-mail: Smiesko@fpharm.uniba.sk

Received: 16 January 2001

Abstract: 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.

Full paper in Portable Document Format: 562a138.pdf

Chemical Papers 56 (2) 138–143 (2002)