Artículos de revistas
3-Chlorotyramine acting as ligand of the d2 dopamine receptor: molecular modeling, synthesis and d2 receptor affinity
Fecha
2015-02Registro en:
Angelina, Emilio Luis; Andujar, Sebastian Antonio; Moreno, Laura; Garibotto, Francisco Matías; Párraga, Javier; et al.; 3-Chlorotyramine acting as ligand of the d2 dopamine receptor: molecular modeling, synthesis and d2 receptor affinity; Wiley VCH Verlag; Molecular Informatics; 34; 1; 2-2015; 28-43
1868-1743
1868-1751
Autor
Angelina, Emilio Luis
Andujar, Sebastian Antonio
Moreno, Laura
Garibotto, Francisco Matías
Párraga, Javier
Peruchena, Nelida Maria
Cabedo, Nuria
Villeco, Margarita
Cortes, Diego
Enriz, Ricardo Daniel
Resumen
We synthesized and tested 3-chlorotyramine as a ligand of the D2 dopamine receptor. This compound displayed a similar affinity by this receptor to that previously reported for dopamine. In order to understand further the experimental results we performed a molecular modeling study of 3-chlorotyramine and structurally related compounds. By combining molecular dynamics simulations with semiempirical (PM6), ab initio and density functional theory calculations, a simple and generally applicable procedure to evaluate the binding energies of these ligands interacting with the D2 dopamine receptors is reported here. These results provided a clear picture of the binding interactions of these compounds from both structural and energetic view points. A reduced model for the binding pocket was used. This approach allowed us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the Quantum Theory of Atoms in Molecules (QTAIM) technique. Molecular aspects of the binding interactions between ligands and the D2 dopamine receptor are discussed in detail. A good correlation between the relative binding energies obtained from theoretical calculations and experimental IC50 values was obtained. These results allowed us to predict that 3-chlorotyramine possesses a significant affinity by the D2-DR. Our theoretical predictions were experimentally corroborated when we synthesized and tested 3-chlorotyramine which displayed a similar affinity by the D2-DR to that reported for DA.