Halogen Bonding Hot Spots as a Constraint in Virtual Screening: A Case Study of 5‑HT₇R

The recently developed and used molecular modeling approach
to
search for privileged amino acids for halogen bonding (XB hot spots)
through XSAR sets has been applied to 5-HT7R. Herein, among
all identified 5-HT7R XB hot spots, the S5x42 was employed
in a virtual screening protocol as a constraint. Through a designed
virtual screening protocol, 63 XSAR sets (156 compounds) were selected
from more than 8 million commercially available compounds and examined
using in vitro assay toward 5-HT7R. A 68% accuracy was
found in predicting halogenated derivatives with higher affinity for
5-HT7R than their unsubstituted analogs. Moreover, it was
observed that a halogen bond formed between S5x42 and a chlorine atom
at the 3-position of the arylpiperazine fragment caused the most remarkable,
35.4-fold increase in binding affinity for 5-HT7R when
compared to the nonhalogenated analog. Interestingly, molecular dynamics
simulations showed the formation of a bifurcated halogen bond with
S5x42.