Computational analysis of ligand recognition sites of homo- and heteropentameric 5-HT3 receptors

Inhibition of the 5-hydroxytryptamine receptor (5-HT3R), a member of the Cys-loop superfamily of Ligand-Gated Ion Channels (LGICs), has been recognized to have important antiemetic effects. With respect to the many other drugs already in use, such as the first generation 5-HT3R antagonist granisetron, palonosetron, a second generation antagonist, clearly demonstrates superior inhibition potency towards the 5-HT(3)Rs. Five different receptor monomers, the 5-HT3R A-E, have been identified although the A and B subunits are the only known to build functional receptors, the homopentameric 5-HT3AR and the heteropentameric 5-HT3B-AR (with BBABA subunit arrangement). At present, however, no three-dimensional structure has been reported for any of the 5-HT3R subunits. To understand the binding properties of agonists and antagonists, models of the extracellular portion of the 5-HT3R A and B subunits are built and assembled into the receptor (homo- and hetero-) pentameric structure on the basis of the known three-dimensional structure of the nicotinic-acetylcholine receptor (nACh-R). The results of docking studies of the natural agonist serotonin and the antagonists palonosetron and granisetron into the modelled homomeric and heteromeric 5-HT3R binding interfaces, provide a possible rationalization both of the higher potency of palonosetron with respect to other antagonists, and of its previously reported allosteric binding and positive cooperativity properties. (C) 2010 Elsevier Masson SAS. All rights reserved.