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Molecular dynamics simulations of sulfone derivatives in complex with DNA topoisomerase IIα ATPase domain
Journal of Biomolecular Structure and Dynamics ( IF 4.4 ) Pub Date : 2020-10-22 , DOI: 10.1080/07391102.2020.1831961
Kanika Verma, Panupong Mahalapbutr, Atima Auepattanapong, Onnicha Khaikate, Chutima Kuhakarn, Kaito Takahashi, Thanyada Rungrotmongkol

Abstract

Human topoisomerase II alpha (TopoIIα) is a crucial enzyme involved in maintaining genomic integrity during the process of DNA replication and mitotic division. It is a vital therapeutic target for designing novel anticancer agents in targeted cancer therapy. Sulfones, members of organosulfur compounds, have been reported to possess various biological activities such as antimicrobial, anti-inflammatory, anti-HIV, anticancer, and antimalarial properties. In the present study, a series of sulfones was selected to evaluate their inhibitory activity against TopoIIα using computational approaches. Molecular docking results revealed that several sulfone analogs bind efficiently to the ATPase domain of TopoIIα. Among them, sulfones 18a, 60a, *4 b, *8 b, *3c, and 8c exhibit higher binding affinity than the known TopoII inhibitor, salvicine. Molecular dynamics simulations and free energy calculations based on MM/PB(GB)SA method demonstrated that sulfone *8 b strongly interacts with amino acid residues in the ATP-binding pocket (E87, N91, D94, I125, I141, F142, S149, G161, and A167), driven mainly by an electrostatic attraction and a strong H-bond formation at G161 residue. Altogether, the obtained results predicted that sulfones could have a high potential to be a lead molecule for targeting TopoIIα.

Communicated by Ramaswamy H. Sarma



中文翻译:

砜衍生物与 DNA 拓扑异构酶 IIα ATPase 结构域复合物的分子动力学模拟

摘要

人类拓扑异构酶 II α (TopoIIα) 是在 DNA 复制和有丝分裂过程中参与维持基因组完整性的关键酶。它是在靶向癌症治疗中设计新型抗癌药物的重要治疗靶点。据报道,砜类是有机硫化合物的成员,具有多种生物活性,如抗菌、抗炎、抗 HIV、抗癌和抗疟特性。在本研究中,选择了一系列砜类来使用计算方法评估它们对 TopoIIα 的抑制活性。分子对接结果显示,几种砜类似物有效地结合到 TopoIIα 的 ATPase 结构域。其中,砜类 18a、60a、*4b、*8b、*3c 和 8c 表现出比已知的 TopoII 抑制剂 salvicine 更高的结合亲和力。基于 MM/PB(GB)SA 方法的分子动力学模拟和自由能计算表明,砜 *8 b 与 ATP 结合口袋(E87、N91、D94、I125、I141、F142、S149、 G161 和 A167),主要由静电吸引力和 G161 残基处的强 H 键形成驱动。总之,所获得的结果预测,砜可能具有成为靶向 TopoIIα 的先导分子的高潜力。

由 Ramaswamy H. Sarma 传达

更新日期:2020-10-22
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