Molecular modeling study of isoindolines as L-type Ca2+ channel blockers by docking calculations |
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Authors: | Teresa Mancilla-Percino José Correa-Basurto José Trujillo-Ferrara Fernando R Ramos-Morales Mario E Acosta Hernández Jesús S Cruz-Sánchez Margarita Saavedra-Vélez |
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Institution: | 1. Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, C.P. 07000, México D.F., México 2. Instituto Politécnico Nacional, Escuela Superior de Medicina, Sección de Estudios de Posgrado e Investigación, Departamento de Bioquímica, Departamento de Farmacología, Plan de San Luis y Díaz Mirón s/n Col. Casco de Santo Tomás, Delegación Miguel Hidalgo, C.P. 11340, México D.F., México 3. Unidad de Servicios de Apoyo en Resolución Analítica, Universidad Veracruzana, Circuito Gonzalo Aguirre Beltrán s/n Zona Universitaria, C.P. 91000, Xalapa, Ver., México 4. Instituto de Ciencias Básicas, Universidad Veracruzana, Circuito Gonzalo Aguirre Beltrán s/n Zona Universitaria, C.P. 91000, Xalapa, Ver., México 5. Facultad de Química Farmacéutica Biológica, Universidad Veracruzana, Circuito Gonzalo Aguirre Beltrán s/n Zona Universitaria, C.P. 91000, Xalapa, Ver., México
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Abstract: | Two series of isoindolines 1(a–g) and 2(a–g) were found by docking calculations to be possible L-type Ca2+ channel (LCC) blockers. The theoretical 3-D model of the outer vestibule and the selective filter of the LCC was provided
by Professor Lipkind; this model consists of transmembrane segments S5 and S6 and P-loops contributed by each of four repeats
(I, II, III, and IV) of Cav 1.2. Therefore, two well-known LCC blockers, nifedipine 3 and (R)-ethosuccinimide 4 were also evaluated, and their binding sites on the LCC were identified and compared with those obtained for 1(a–g) and 2(a–g). Analysis of the results shows that the target compounds tested probably could be LCC blockers, since they interact with
or near the glutamic acid residues Glu393, Glu736, Glu1145 and Glu1446 (the EEEE locus), which belong to the LCC selectivity
region. The ∆G values for all of the Ca2+ channel ligands are between−10.78 and −3.67 (kcal mol−1), showing that LCC-1b, -1e and -1f complexes are more stable than the other compounds tested. Therefore, theoretically calculated dissociation constants K
d (μM) were obtained for all compounds. Comparing these values reveals that compounds 1b (0.0244 μM), 1e (0.0176 μM) and 1f (0.0125 μM) exhibit more affinity for the LCC than the other compounds. This screening shows that the two series of isoindolines
probably could act as LCC blockers. |
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