Abstract

The DNA topoisomerase enzymes, Topo I and Topo II, have been used as molecular targets for drug design of anticancer agents. The search is for new anticancer therapies that respond to the toxicity of current drug treatments and tumor resistance. The present study provides insights into a likely dual inhibitory effect on Topo I and II of trifluoromethylsulfonamide (triflamide) derivatives by computational docking studies. The physicochemical properties of these compounds were evaluated by Lipinski’s rules. Molecular docking simulations were conducted to determine the possible molecular target, mode and energy binding of the triflamide derivatives. An in silico analysis indicated that the triflamide derivatives interact with amino acid residues at the active site of Topo I and Topo II. The highest binding energy for the Topo I complex was shown by 1g and for the Topo II complex by 1e; these studies were validated by the analysis of decoys. Virtual mutations of Topo I and Topo II were tested, revealing the importance of certain active site residues on the binding mode and binding energy of the test triflamide derivatives. Overall, the results suggest that the compounds 1g and 1e could be drugs promising for the future design and development of anticancer agents.

Graphic abstract

Analysis of physicochemical, toxicological and pharmacokinetic properties of triflamide derivatives and their interactions with DNA topoisomerase I and II enzymes (Topo I and II) have been reported in this study. These computational results indicated that triflamide derivatives could present a dual inhibition by binding to the active site of both enzymes, validated by decoys analysis. On the other hand, the generation of virtual mutants of Topo I and II demonstrated the great influence of certain amino acids on the mode of union of triflamides.

中文翻译：

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探索三聚体衍生物在Topo I和Topo II酶活性位点的结合模式：计算机分析和精确的分子对接

摘要

DNA拓扑异构酶，Topo I和Topo II，已被用作抗癌药物设计的分子靶标。寻求新的抗癌疗法，以应对当前药物治疗的毒性和肿瘤耐药性。通过计算对接研究，本研究提供了对三氟甲基磺酰胺（triflamide）衍生物对Topo I和II可能双重抑制作用的见解。这些化合物的理化性质通过Lipinski规则进行评估。进行了分子对接模拟，以确定三氟化物衍生物的可能的分子靶标，模式和能量结合。一个在硅片分析表明三氟化物衍生物与在Topo I和Topo II的活性位点的氨基酸残基相互作用。Topo I配合物的最高结合能以1g表示，Topo II配合物的最高结合能以1e表示；这些研究通过诱饵分析得到了验证。测试了Topo I和Topo II的虚拟突变，揭示了某些活性位点残基对被测三氟化物衍生物的结合方式和结合能的重要性。总体而言，结果表明化合物1g和1e可能是抗癌剂未来设计和开发的有希望的药物。

图形摘要

这项研究已经报道了三氟化物衍生物的理化，毒理和药代动力学特性及其与DNA拓扑异构酶I和II酶（Topo I和II）的相互作用的分析。这些计算结果表明三氟化物衍生物可以通过结合两种酶的活性位点而表现出双重抑制作用，并通过诱饵分析进行了验证。另一方面，Topo I和II的虚拟突变体的产生证明某些氨基酸对三氟化物的结合模式有很大的影响。