Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México D.F., México.
J Mol Model. 2010 Aug;16(8):1377-82. doi: 10.1007/s00894-010-0643-6. Epub 2010 Feb 12.
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.
通过对接计算，发现两个系列的异吲哚啉 1(a-g)和 2(a-g)可能是 L 型钙 (Ca(2+)) 通道 (LCC) 阻滞剂。Lipkind 教授提供了 LCC 外腔和选择性滤波器的理论 3D 模型；该模型由跨膜片段 S5 和 S6 以及每个 Ca(v)1.2 的四个重复 (I、II、III 和 IV) 贡献的 P 环组成。因此，还评估了两种已知的 LCC 阻滞剂，硝苯地平 3 和 (R)-ethosuccinimide 4，并确定了它们在 LCC 上的结合位点，并与 1(a-g)和 2(a-g)的结合位点进行了比较。结果分析表明，所测试的靶化合物可能是 LCC 阻滞剂，因为它们与属于 LCC 选择性区域的谷氨酸残基 Glu393、Glu736、Glu1145 和 Glu1446（EEEE 位点）相互作用或靠近它们。所有钙 (Ca(2+)) 通道配体的 G 值在-10.78 和-3.67（kcal mol(-1)) 之间，表明 LCC-1b、-1e 和-1f 复合物比其他测试化合物更稳定。因此，获得了所有化合物的理论计算解离常数 K(d)（微摩尔）。比较这些值表明，化合物 1b（0.0244 微摩尔）、1e（0.0176 微摩尔）和 1f（0.0125 微摩尔）对 LCC 的亲和力大于其他化合物。这种筛选表明，这两个系列的异吲哚啉可能作为 LCC 阻滞剂发挥作用。
