title: Unusual bond formation in aspartic protease inhibitors: a theoretical study.
abstract: The origin of the formation of the weak bond N|C...O involved in an original class of aspartic protease inhibitors was investigated by means of the electron localization function (ELF) and explicitly correlated wave-function (MRCI) analysis. The distance between the electrophilic C and the nucleophilic N centers appears to be controlled directly by the polarity and proticity of the medium. In light of these investigations, an unusual dative N-C bonding picture was characterized. Formation of this bond is driven by the enhancement of the ionic contribution C(+)-O(-) induced mainly by the polarization effect of the near N lone pair, and to a lesser extent by a weak charge delocalization N-->CO. Although the main role of the solvating environment is to stabilize the ionic configuration, the protic solvent can enhance the C(+)-O(-) configuration through a slight but cumulative charge transfer towards water molecules in the short N-C distance regime. Our revisited bond scheme suggests the possible tuning of the N-CO interaction in the design of specific inhibitors.
authors: Laboratoire de Chimie, UMR CNRS 5182, Ecole Normale Supérieure de Lyon, 46 Allée d'Italie, 69364 Lyon Cedex 07, France.
authors: Julien
authors: J
authors: Pilmé
authors: Hélène
authors: H
authors: Berthoumieux
authors: Vincent
authors: V
authors: Robert
authors: Paul
authors: P
authors: Fleurat-Lessard
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000737:chemistry*; D003198:Computer Simulation; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry*; D011789:Quantum Theory
chemical_list: D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases