Exploring Halogen Bonds in 5‑Hydroxytryptamine 2B Receptor–Ligand Interactions

Here, we predicted the potential
halogen bonding interaction between
compound 2 and the 5-hydroxytryptamine 2B (5-HT2B) receptor and systematically assessed this interaction via structure–activity
relationship analysis and molecular dynamics simulations. A physics-based
computational protocol was then developed to further explore the opportunity
of “designing in” halogen bonding interactions in structure-based
ligand design for the 5-HT2B receptor, which not only facilitated
the identification of previously uncharacterized halogen bonds in
known 5-HT2B ligands but also enabled the rational design
of halogen bonding interactions for the optimization of 5-HT2B ligands. As a proof-of-concept, a series of halogen-substituted
analogues of doxepin was synthesized and evaluated, which showed improved
in vitro and in vivo potency.