Merlino Alicia, Otero Lucia, Gambino Dinorah, Laura Coitiño E
Laboratorio de Química Teórica y Computacional, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
Eur J Med Chem. 2011 Jul;46(7):2639-51. doi: 10.1016/j.ejmech.2011.03.046. Epub 2011 Apr 2.
In order to rationalize the available data related to the antichagasic activity of Pt/Pd complexes containing 5-nitrofurylthiosemicarbazones, in the present work we carried out a PCM/DFT comparative characterization of 16 Pt(II)/Pd(II) compounds of general formula [MCl(2)L] and the corresponding 5-nitrofurylthiosemicarbazone ligands (L) using multivariate techniques to sort and classify them and to search for patterns correlating the biological activity with calculated physicochemical descriptors. The data allow us to rationally propose that these compounds might act through dual or even multiple mechanisms of action, with preferred paths that depend on both the nature of metal and ligand. Moreover, these results suggest that the complexes in the set would not react in vivo with DNA, being biotransformed earlier, before gaining access to nuclear DNA in the cell. The binding mode and inhibitory potency of a selection of metal complexes and ligands with Trypanosoma cruzi cruzipain and trypanothione reductase enzymes is also modeled through molecular docking.
为了使与含5-硝基呋喃硫代半卡巴腙的铂/钯配合物的抗恰加斯病活性相关的现有数据合理化，在本工作中，我们使用多变量技术对通式为[MCl₂L]的16种铂(II)/钯(II)化合物以及相应的5-硝基呋喃硫代半卡巴腙配体(L)进行了PCM/DFT比较表征，以对它们进行分类和排序，并寻找将生物活性与计算出的物理化学描述符相关联的模式。这些数据使我们能够合理地提出，这些化合物可能通过双重甚至多种作用机制起作用，其优先途径取决于金属和配体的性质。此外，这些结果表明，该组中的配合物在体内不会与DNA反应，而是在进入细胞中的核DNA之前更早地进行生物转化。还通过分子对接对一系列金属配合物和配体与克氏锥虫克鲁齐蛋白酶和锥虫硫醇还原酶的结合模式和抑制效力进行了建模。
