Heteroaromatic π-stacking energy landscapes

J Chem Inf Model. 2014 May 27;54(5):1371-9. doi: 10.1021/ci500183u. Epub 2014 May 9.

Abstract

In this study we investigate π-stacking interactions of a variety of aromatic heterocycles with benzene using dispersion corrected density functional theory. We calculate extensive potential energy surfaces for parallel-displaced interaction geometries. We find that dispersion contributes significantly to the interaction energy and is complemented by a varying degree of electrostatic interactions. We identify geometric preferences and minimum interaction energies for a set of 13 5- and 6-membered aromatic heterocycles frequently encountered in small drug-like molecules. We demonstrate that the electrostatic properties of these systems are a key determinant for their orientational preferences. The results of this study can be applied in lead optimization for the improvement of stacking interactions, as it provides detailed energy landscapes for a wide range of coplanar heteroaromatic geometries. These energy landscapes can serve as a guide for ring replacement in structure-based drug design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzene / chemistry*
  • Drug Design
  • Heterocyclic Compounds / chemistry*
  • Models, Molecular*
  • Molecular Conformation
  • Pharmaceutical Preparations / chemistry
  • Quantum Theory*
  • Static Electricity
  • Thermodynamics

Substances

  • Heterocyclic Compounds
  • Pharmaceutical Preparations
  • Benzene