Scaffold dependencies for halogen bonding: quantum mechanical investigation of nitrogen-bearing heterocycles

Halogen bonding is a rather new but promising type of interaction for the drug discovery process. It is rather directional and involves an electron donor as binding partner. Employing quantum chemical calculations [1-3], we explore the applicability of halogen bonds in molecular design with respect to halogen-enriched fragment libraries (HEFlibs) [4]. Computational studies on protein-ligand complexes have been reported indicating varying halogen-bond strengths that depend on the chemical nature of the ligand and the surrounding binding pocket. The strength and behavior of a halogen bond certainly depends on the core scaffold to which the halogen is attached. Due to the relative novelty of halogen bonding in medicinal chemistry, only a few experimental studies exist [4-6]. Therefore, we computed 30 different nitrogen-bearing heterocycles substituted by chlorine, bromine, or iodine (in total 459 structures) to increase our understanding of scaffold-based tuning of halogen bonds (see Figure 1 below for a few examples). For each structure the electrostatic-potential isosurfaces