title: Targeting histidine side chains in molecular design through nitrogen-halogen bonds.
abstract: Halogen bonds are directional noncovalent interactions that can be used to target electron donors in a protein binding site. In this study, we employ quantum chemical calculations to explore halogen···nitrogen contacts involving histidine side chains. We characterize the energetics on the MP2 level of theory using SCS-MP2 and CCSD(T)/CBS as reference calculations and elucidate their energy profile in suboptimal geometries. We derive simple rules allowing medicinal chemists and chemical biologists to easily determine preferred areas of interaction in a binding site and exploit them for scaffold decoration and design. Our work shows that nitrogen-halogen bonds are valuable interactions that are this far underexploited in patent applications, lead structure, and clinical candidate selection. We highlight their potential to increase binding affinities and suggest that they can significantly contribute to inducing and tuning subtype selectivities.
authors.affiliation: Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lange
authors.forename: Markus O
authors.initials: MO
authors.lastname: Zimmermann
authors.forename: Rainer
authors.initials: R
authors.lastname: Wilcken
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahn
authors.forename: Frank M
authors.initials: FM
authors.lastname: Boeckler
mesh_terms: D001969:Bromobenzenes / Q000737:chemistry*; D002722:Chlorobenzenes / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000737:chemistry; D006639:Histidine / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007462:Iodobenzenes / Q000737:chemistry*; D008024:Ligands; D008956:Models, Chemical; D011789:Quantum Theory; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D001969:Bromobenzenes; D002722:Chlorobenzenes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007462:Iodobenzenes; D008024:Ligands; D006639:Histidine; C029899:imidazole; C031905:iodobenzene; C032036:bromobenzene; D051231:Farnesyltranstransferase; C031294:chlorobenzene