Molecular modeling study of isoindolines as L-type Ca(2+) channel blockers by docking calculations.

Two series of isoindolines 1(a-g) and 2(a-g) were found by docking calculations to be possible L-type Ca(2+) 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 Ca(v) 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 Ca(2+) 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) (microM) were obtained for all compounds. Comparing these values reveals that compounds 1b (0.0244 microM), 1e (0.0176 microM) and 1f (0.0125 microM) 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.