Heteroaromatic π-stacking energy landscapes.
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.
Institute of General, Inorganic and Theoretical Chemistry, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , CCB - Center for Chemistry and Biomedicine, Innrain 80/82, A-6020 Innsbruck, Austria.
Roland G
RG
Huber
Michael A
MA
Margreiter
Julian E
JE
Fuchs
Susanne
S
von Grafenstein
Christofer S
CS
Tautermann
Klaus R
KR
Liedl
Thomas
T
Fox
D001554:Benzene / Q000737:chemistry*; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D004364:Pharmaceutical Preparations / Q000737:chemistry; D011789:Quantum Theory; D055672:Static Electricity; D013816:Thermodynamics
D006571:Heterocyclic Compounds; D004364:Pharmaceutical Preparations; D001554:Benzene