Publication of a crystal structure of ß₂-adrenergic receptor in November of 2007 [1] seems to be a long awaited breakthrough in discovering three dimensional structure of G-protein coupled receptors, especially in the monoaminergic subgroup. ß₂-adrenergic receptor is the second G-protein coupled receptor ever crystalallized and described using rentgenographic methods, after bovine rhodopsin, resolved in 2000 [2]. The newly-published structure revealed fair similarity to the models of monoaminergic receptors obtained on the template of bovine rhodopsin, however some explicit topological differences could be observed. In spite of the fact that localization and shape of the binding site were very similar, divergences in the spatial distribution of the most important interaction points seemed to have potentially significant impact on the ligand recognition pattern.

Considering the fact, that ß₂-adrenergic receptor is much more related to the investigated serotonin receptors, especially taking into account the sequence homology of the binding sites, we decided to obtain the homology models of 5-HT_1A and 5-HT_2A receptors using the novel template. Molecular models were built with Modeller 8v2 software, which allowed the conformational sampling of the binding site, by means of simulated annealing. In order to compare the lignand binding mode and asses the possible benefits of using the novel template, we performed the analysis of ligand-receptor interactions, with the use of docking procedure.

Ligands with known 5-HT_1A and 5-HT_2A receptor affinity were automatically docked to the multiconformational sets of the obtained receptor models, using both Glide and FlexX software, with and without pharmacophore constraints. Docking was performed with both conformationaly rigidified and flexible compounds, derived from litrerature or synthesized in Department of Pharmeceutical Chemistry. The obtained results were discussed in comparison with data on previously published (5-HT_1A) [3] or newly obtained (5-HT_2A) rhodopsin-based models.

References:
[1] Cherezov V, Rosenbaum DM, et al. Science. 2007 Nov 23;318(5854):1258-65.
[2] Palczewski K, Kumasaka T, et al. Science. 2000 Aug 4;289(5480):739-45.
[3] Nowak M, Kołaczkowski M, et al. J Med Chem. 2006 Nov 16;49(23):6732-41.

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