Application of Hybrid Density Functional Theory in Calculation of Edge-to-Face Interactions of Receptor-Ligand System

Vladimir V. Šukalović,¹ Mario V. Zlatović,^2,* Goran M. Roglić,² Slađana V. Kostić-Rajačić¹ and Deana B. Andrić²

¹ IHTM Department of Chemistry, University of Belgrade, POB 473, 11001 Belgrade, Serbia
² Faculty of Chemistry, University of Belgrade, POB 51, 11158 Belgrade 118, Serbia
* Corresponding author: E-mail: mario@chem.bg.ac.rs
Phone: +381-11-2639-751, fax: +381-11-2636-061

Abstract
Our previously described research on docking analysis of a series of isosteric N4-arylpiperazines on a model of 5-HT_1A receptor was used earlier to investigate interactions of different ligands with the receptor binding site. Due to the limitations of molecular mechanics (MM) methods, docking analysis failed to give precise results about interactions that influence binding affinity of the ligands, but we presumed that aromatic-aromatic interactions, or edge-to-face, to be more precise, play an important role in the binding process. In order to further elaborate on this hypothesis, ab initio approach was used to calculate possible edge-to-face interactions on a model system and correlate them to ligand affinity. Obtained results indicate that those dispersive interactions can show notable influence on the binding of the ligands to 5-HT_1A receptor. Stabilization energies of modeled receptor-ligand complex, calculated using Becke’s “half-and-half” hybrid DFT method showed strong correlation with the affinity of investigated ligands towards 5-HT_1A receptor.

Keywords: Hybrid DFT; ligand affinity; correlation; 5-HT_1A