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

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.