Damercheli Maryam, Mahdi Mahdi, Mehravi Bita, Shafiee Ardestani Mehdi
Department of Inorganic Chemistry, Faculty of Chemistry, Semnan University, Semnan, Iran.
Department of Medical Nanotechnology, Faculty of Advanced Technology in Medicine, Iran University of Medical Sciences, Tehran, Iran.
Iran J Pharm Res. 2019 Fall;18(4):2055-2066. doi: 10.22037/ijpr.2019.12792.11151.
Although metal-based anticancer drugs have been recognized as the most effective agents over the organic compounds, non-selectivity and high toxic effects have limited their applications in a way that only three Pt-analogues have progressed into clinical use. These problems have spurred chemists to develop different strategies based on alternative targets. This work focuses on predicting potency and mode of interactions of a series of salen type Schiff base transition metal complexes derived from meso-1,2-diphenyl-1,2-ethylenediamine, over some proteins (HDAC7, HDAC2, CatB, B-RAF kinase, TopII, RNR, TS, and rHA) using computational docking method, to be later considered as possible anticancer agents. The obtained results showed that all complexes exhibited higher affinity for HDAC7 than the other targets. Moreover, the bromo-derivatives of the copper compounds were more active on HDAC7 than the other derivatives. Such bromo compounds showed considerable interactions with Kinase, RNR, TS, and CatB. Contrary to Histone deacetylase (HAD)C7; HDAC2 was predicted to be relatively poor target. As expected, formation of the hydrophobic interactions between the metal complexes and the protein targets were essential for activity of the metal compounds. This study provides some more information for further optimizations and development of new metallodrugs as enzyme inhibitors for potential therapeutic agents.
尽管金属基抗癌药物被认为是比有机化合物更有效的药物，但非选择性和高毒性限制了它们的应用，目前只有三种铂类似物进入临床使用。这些问题促使化学家基于其他靶点开发不同的策略。这项工作重点是使用计算对接方法预测一系列由内消旋-1,2-二苯基-1,2-乙二胺衍生的席夫碱型过渡金属配合物与某些蛋白质（HDAC7、HDAC2、组织蛋白酶B、B-RAF激酶、拓扑异构酶II、核糖核苷酸还原酶、胸苷合成酶和重组人血管生成素）之间的活性和相互作用模式，以便后续将其视为可能的抗癌药物。所得结果表明，所有配合物对HDAC7的亲和力均高于其他靶点。此外，铜化合物的溴衍生物对HDAC7的活性高于其他衍生物。此类溴化合物与激酶、核糖核苷酸还原酶、胸苷合成酶和组织蛋白酶B表现出显著的相互作用。与组蛋白去乙酰化酶（HAD）C7相反；HDAC2预计是相对较差的靶点。正如预期的那样，金属配合物与蛋白质靶点之间形成疏水相互作用对金属化合物的活性至关重要。这项研究为进一步优化和开发新型金属药物作为潜在治疗剂的酶抑制剂提供了更多信息。
