Scior Thomas, Mack Hans-Georg, García José Antonio Guevara, Koch Wolfhard
Departamento de Farmacia, Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Colonia San Manuel, Puebla, Mexico.
Drug Des Devel Ther. 2009 Feb 6;2:221-31.
The postulated transition of Bis-Maltolato-OxoVanadium(IV) (BMOV) from its inactive trans- into its cis-aquo-BMOV isomeric form in solution was simulated by means of computational molecular modeling. The rotational barrier was calculated with DFT - B3LYP under a stepwise optimization protocol with STO-3G, 3-21G, 3-21G*, and 6-31G ab initio basis sets. Our computed results are consistent with reports on the putative molecular mechanism of BMOV triggering the insulin-like cellular response (insulin mimetic) as a potent inhibitor of the protein tyrosine phosphatase-1B (PTP-1B). Initially, trans-BMOV is present in its solid dosage form but in aqueous solution, and during oral administration, it is readily converted into a mixture of "open-type" and "closed-type" complexes of cis-aquo-BMOV under equilibrium conditions. However, in the same measure as the "closed-type" complex binds to the cytosolic PTP-1B, it disappears from solution, and the equilibrium shifts towards the "closed-type" species. In full accordance, the computed binding mode of cis-BMOV is energetically favored over sterically hindered trans-BMOV. In view of our earlier report on prodrug hypothesis of vanadium organic compounds the present results suggest that cis-BMOV is the bioactive species.
通过计算分子模拟，对双麦芽酚氧钒（IV）（BMOV）在溶液中从无活性的反式转变为顺式水合BMOV异构体形式的假设转变进行了模拟。在使用STO-3G、3-21G、3-21G*和6-31G从头算基组的逐步优化协议下，用DFT - B3LYP计算了旋转势垒。我们的计算结果与关于BMOV作为蛋白酪氨酸磷酸酶-1B（PTP-1B）的有效抑制剂引发胰岛素样细胞反应（胰岛素模拟）的假定分子机制的报道一致。最初，反式BMOV以其固体剂型存在，但在水溶液中，并且在口服给药期间，在平衡条件下它很容易转化为顺式水合BMOV的“开放型”和“封闭型”复合物的混合物。然而，与“封闭型”复合物与胞质PTP-1B结合的程度相同，它从溶液中消失，并且平衡向“封闭型”物种移动。完全一致的是，计算出的顺式BMOV的结合模式在能量上比空间位阻较大的反式BMOV更有利。鉴于我们早期关于钒有机化合物前药假说的报告，目前的结果表明顺式BMOV是生物活性物种。
