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

Yu Zhou#Yuanxun Wang‡†#Pengfei LiXi-Ping Huang§Xiangbin Qi†∥ , Yunfei Du* , and Niu Huang*†∥

National Institute of Biological Sciences, Beijing 102206, China
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
§ Department of Pharmacology, The National Institute of Mental Health Psychoactive Drug Screening Program (NIMH-PDSP), The University of North Carolina, Chapel Hill, North Carolina 27759, United States
Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China


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.