Luna-Palencia Gabriela R, Martinez-Ramos Federico, Vasquez-Moctezuma Ismael, Fragoso-Vazquez Manuel Jonathan, Mendieta-Wejebe Jessica Elena, Padilla-Martínez Itzia I, Sixto-Lopez Yudibeth, Mendez-Luna David, Trujillo-Ferrara Jose, Meraz-Rios Marco A, Fonseca-Sabater Yadira, Correa-Basurto Jose
Molecular Modeling and Drug Design Laboratory, Biophysics and Biocatalysis Lab, Biochemistry Lab, Seccion de Estudios de Posgrado e Investigacion y Departamento de Bioquimica, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron, Distrito Federal 11340, Mexico.
Anticancer Agents Med Chem. 2014;14(7):984-93. doi: 10.2174/1871520614666140127113218.
Valproic acid (VPA) is extensively used as an anticonvulsive agent and as a treatment for other neurological disorders. It has been shown that VPA exerts an anti-proliferative effect on several types of cancer cells by inhibiting the activity of histone deacetylases (HDACs), which are involved in replication and differentiation processes. However, VPA has some disadvantages, among which are poor water solubility and hepatotoxicity. Therefore, the aim of the present study was to design and synthesize three derivatives of VPA to improve its physicochemical properties and anti-proliferative effects. For this purpose, the amino acids aspartic acid, glutamic acid and proline were added to the molecular structure of VPA. Docking and molecular dynamics simulations were used to determine the mode of recognition of these three derivatives by different conformations of HDAC8. This receptor was used as the specific target because of its high affinity for this type of substrate. The results demonstrate that, compared to VPA, the test compounds bind to different sites on the enzyme and that hydrogen bonds and hydrophobic interactions play key roles in this difference. The IC50 values of the VPA derivatives, experimentally determined using HeLa cells, were in the mM range. This result indicates that the derivatives have greater antiproliferative effects than the parent compound. Hence, these results suggest that these amino acid derivatives may represent a good alternative for anticancer treatment.
丙戊酸（VPA）被广泛用作抗惊厥剂以及治疗其他神经系统疾病。研究表明，VPA通过抑制参与复制和分化过程的组蛋白脱乙酰酶（HDACs）的活性，对多种类型的癌细胞发挥抗增殖作用。然而，VPA存在一些缺点，其中包括水溶性差和肝毒性。因此，本研究的目的是设计并合成VPA的三种衍生物，以改善其理化性质和抗增殖效果。为此，将天冬氨酸、谷氨酸和脯氨酸添加到VPA的分子结构中。采用对接和分子动力学模拟来确定HDAC8的不同构象对这三种衍生物的识别模式。由于该受体对这类底物具有高亲和力，因此将其用作特异性靶点。结果表明，与VPA相比，受试化合物与酶上的不同位点结合，氢键和疏水相互作用在这种差异中起关键作用。使用HeLa细胞通过实验测定的VPA衍生物的IC50值在毫摩尔范围内。这一结果表明，这些衍生物比母体化合物具有更强的抗增殖作用。因此，这些结果表明这些氨基酸衍生物可能是抗癌治疗的一个良好选择。
