Heteroaromatic π-stacking energy landscapes.

Roland G Huber,Michael A Margreiter,Thomas Fox,Susanne Von Grafenstein,Julian E Fuchs,Christofer S Tautermann,Klaus R Liedl

doi:10.1021/ci500183u

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.

Highlights

Heteroaromatic rings are a key component in most known drug molecules.[1]
Results obtained using ωB97XD/cc-pVTZ were consistently within less than 0.5 kcal/mol compared to CCSD(T)/complete basis set (CBS) calculations for stacked geometries and CCSD(T)/cc-pVTZ calculations of paralleldisplaced geometries
Manual optimization was performed by displacing the aromatic heterocycle from the stacked minimum along the X direction in steps of 0.1 Å while keeping the benzene at the origin stationary

Summary

Introduction

Heteroaromatic rings are a key component in most known drug molecules.[1]. They provide rigid building blocks for anchoring substituents in defined geometric positions, thereby determining the overall molecular shape. Their unique interactions are a reason for their frequent occurrence in natural as well as synthetic bioactive molecules

Methods

Results

Conclusion