Ab-initio study of pyrrole ring deformation in the indole group of 5-HT interacting with water molecules

5-Hydroxytryptamine (5-HT; serotonin) regulates metabolism and various homeostatic mechanisms in the body, and is involved in depression. These complicated functions of 5-HT are supported by several 5-HT receptor and 5-HT transporter subtypes. The development of agonists/antagonists and activators/inhibitors of 5-HT receptors and transporters is a strong target for drug studies. Toward this purpose, we calculated the conformations and electrical states of ionized 5-HT in aqueous solution using ab-initio methods. When we assumed an ionized 5-HT molecule and three surrounding water molecules, the hydrogen bond network for these four molecules formed a ring shape, resulting in deformation of the pyrrole ring in the indole group of 5-HT. To our knowledge, this is the first finding demonstrating deformation of the indole skeleton. The findings suggest that the direct involvement of water in the binding between 5-HT and its receptors and transporters should be taken account when designing candidate 5-HT active compounds.