Recently, we have studied halogen bonding contacts with different interaction partners in protein binding sites for their use in molecular design [1-3]. For the successful application of halogen bonding in drug discovery, a better understanding of suitable ligand systems for implementing halogen bonds in medicinal chemistry is likewise required [4-5]. The aromatic scaffold and the attachment position of a halogen will certainly influence the strength of a halogen bond. In addition, it also can modify its geometry based on changes in electron distribution and the formation of additional interactions (binding motifs). In this systematic study, we strive to gain further insights into tuning effects and geometry changes by computing ~450 fragments of 30 different nitrogen-bearing heterocycles substituted by chlorine, bromine or iodine. As a characteristic property of the s-hole, we calculated and visualized the most positive electrostatic potential (Vmax) on the relevant part of the isodensity surface. Adduct formation energies with N-methylacetamide as a small model system for the protein backbone were calculated on a MP2/TZVPP level of theory. Good correlations between the values of Vmax and the adduct formation energies were found. This is in line with previous studies [6]. Other ways to predict the strength of the halogen bond tuning based on this data set will be investigated as well.  References  Wilcken et al., J. Chem. Theory Comput., 2011 , 7 (7), 2307�2315.Wilcken et al., J. Comput. Aided Mol. Des., 2012 , 26, 935�945.Lange et al., J. Chem. Inf. Model, 2013 , 53 (12), 3178-3189.Wilcken et al., J. Med. Chem., 2013 , 56 (4): 1363-1388.Wilcken et al., J. Am. Chem. Soc., 2012 , 134 (15), 6810�6818.Politzer et al., Phys. Chem. Chem. Phys., 2013 , 15, 11178-11189.

Quantum mechanical investigation of scaffold effects on halogen bond strength

248th National Meeting (2014)

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