José Raúl Bahena Herrera
Instituto Politécnico Nacional
México
Title: Evaluation in silico and ex vivo: Determining affinity, selectivity and presumable allosteric modulation of new compounds towards β1/β2 adrenoceptors
Biography
Biography: José Raúl Bahena Herrera
Abstract
Adrenergic receptors are important targets for pharmaceutical development and physiological studies. Although several drugs have been designed as agonist/antagonist for these receptors, the insights for rational design of highly selective molecules are still not widely described nor used. Therefore the aim for the present study was to determine the affinity and selectivity of a series of new rationally designed isoindoline derivatives with β1 / β2 adrenoceptors. We performed a global and local reactivity evaluation of the best ligands with β2 adrenoceptor in order to understand the selectivity of the binding pocket. The results of the in silico experiments suggest that our molecules might be metabolized by CYP450 and they are in agreement with the Lipinski’s rule of five; the docking studies show that the ligands interact with the orthosteric site of β2-adrenoceptors and with the orthosteric and allosteric site of β1 adrenoceptor with more selectivity for the first one. The ex vivo results in the isolated guinea pig trachea model indicates that EC50 for the molecule MD2p13-16 was 2.39 x 10-8 M, with a ΔG of -10.8 ± 1.2 Kcal/Mol. Finally Molecule MD2p13-16 have a higher potency in comparison to albuterol for concentrations 1 x10-10, 1 x 10-9.5, 1 x10-9 and 1 x10-8.5 M; all the above information allows us to propose that the designed drug works as a partial agonist of β2-adrenoceptor and according to Hill's equation we can associate a phenomenon of negative cooperativity.