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.

Curly arrows meet electron density transfers in chemical reaction mechanisms: from electron localization function (ELF) analysis to valence-shell electron-pair repulsion (VSEPR) inspired interpretation

“…The name of quantum chemical topology 49,50 has been introduced to embrace all topological investigations of three-dimensional scalar fields [51][52][53][54][55][56][57][58] to rationalize the chemical bond and further understanding of the chemical reactivity. [59][60][61][62][63][64][65][66][67] A number of excellent works in the subject have been published to remark the importance of charge density analysis applied to chemical and biological systems and solids. 47,48,56,[68][69][70][71][72][73][74] Probing the electron density distribution during a chemical reaction can provide important insights, but this aim has required extension of the relationships between the traditional chemical concepts and the quantum mechanical ones.…”

Chemical structure and reactivity by means of quantum chemical topology analysis

“…QCT has been successfully employed for the analysis of chemical bond as well as to provide a further understanding of the chemical reactivity [131][132][133][134][135][136][137][138]. Likewise, Nasertayoob and Shahbazian [68] have presented an account on the mathematical foundations of the topological analysis of the electronic charge densities while Martín-Pendás et al have presented an outlook on the use of quantum chemical topology techniques in crystallography [63].…”

New Structural Insights into Saraines A, B, and C, Macrocyclic Alkaloids from the Mediterranean Sponge Reniera (Haliclona) sarai

“…The interaction between a nucleophilic tertiary amine and carbonyl group is unusual, but it has been observed for some alkaloids and synthetic compounds, and recently implied in the design and synthesis of systems to be inserted in a peptidomimetic. [13] With the aim to predict the geometries for the amine aldehyde form and its zwitterionic structure we carried out calculations at the B3LYP/6-31+G(d) level of theory [14] for the core structure of saraines A-C, obtained by replacing the two side rings with an H atom at C-3Ј and three methyl groups at N-1, N-1Ј, and C-3 (Scheme 1). The relevant structural parameters evaluated by our calculations on the amine aldehyde model indicated a value of 2.438 Å for the nonbonded N···C=O distance, with an angle of 106.95°, which is in good agreement with the Bürgi-Dunitz model ( Figure 4, structure V).…”