The 5-HT3 and nACh Ionotropic Receptors: A Perspective from the Computational Chemistry Point of View

A.      Morreale; I.      Iriepa; E.      Galvez

doi:10.2174/0929867023371328

Abstract

Recent contributions applying Computational Chemistry to serotonin-3 and nicotinic acetylcholine ionotropic receptors are reviewed. These two receptors constitute a good example for the examination of the computational protocols that have been used to understand how they work. On the one hand, (5-HT3R) receptor mapping techniques have been mostly employed in its study and very few examples of receptor fitting have been appeared. On the other hand, (nAChR) has been studied mainly from the receptor fitting point of view, although many contributions using receptor mapping exist. In the first case, antagonists seems to be more important that agonists, so more works are devo- ted to them. In the second case, agonist development is the main issue. Although far for being complete, in either of the cases we have working pharmacophores as well as 3D models for their binding sites that are ready to be used as a starting guess to design potential drugs. It is noteworthy that the absence of crystallographic structure for these receptors has motivated the interest in their study, constituting an interesting and challenging field. Mutagenesis experiments have allowed the establishment of main amino acids that are essential in the receptor functioning and then, interaction models have been postulated. Although most of the models are speculative in nature, some of them have been proved to be valuable tools for drug design. This scientific field is already open and many areas are still unexplored. Computational tools for treating these issues exist in a wide variety and their rational application would produce the answers to the structure and functioning of these receptors.

Keywords: 5-HT3, nACh Ionotropic Receptors, (nAChR), (S)-Zacopride, Quinazoline-2,4-diones, 1,8-naphthalimides, Tropisetron, Granisetron, Metoclopramide, Zetidoline