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J Med Chem. 2018 Oct 11;61(19):8717-8733. doi: 10.1021/acs.jmedchem.8b00828. Epub 2018 Sep 21.

Amino Acid Hot Spots of Halogen Bonding: A Combined Theoretical and Experimental Case Study of the 5-HT7 Receptor.

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Department of Medicinal Chemistry , Institute of Pharmacology, Polish Academy of Sciences , 12 Smętna Street , 31-343 Krakow , Poland.
Department of Medicinal Chemistry , Jagiellonian University Medical College , 9 Medyczna Street , 30-688 Krakow , Poland.


A computational approach combining a structure-activity relationship library of halogenated and the corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking and binding free energy calculations was used to search for amino acids frequently targeted by halogen bonding (hot spots) in a 5-HT7R as a case study. The procedure identified two sets of hot spots, extracellular (D2.65, T2.64, and E7.35) and transmembrane (C3.36, T5.39, and S5.42), which were further verified by a synthesized library of halogenated arylsulfonamide derivatives of (aryloxy)ethylpiperidines. It was found that a halogen bond formed between T5.39 and a bromine atom at 3-position of the aryloxy fragment caused the most remarkable, 35-fold increase in binding affinity for 5-HT7R when compared to the nonhalogenated analog. The proposed paradigm of halogen bonding hot spots was additionally verified on D4 dopamine receptor showing that it can be used in rational drug design/optimization for any protein target.

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