Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development.,ChemMedChem

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Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-02-11 , DOI: 10.1002/cmdc.201900721
Purushottam B Tiwari ₁ , Prem P Chapagain _{2,

3} , Ahmed Seddek _{3,

4} , Thirunavukkarasu Annamalai _{3,

4} , Aykut Üren ₁ , Yuk-Ching Tse-Dinh _{3,

4}

Affiliation

A topoisomerase-DNA transient covalent complex can be a druggable target for novel topoisomerase poison inhibitors that represent a new class of antibacterial or anticancer drugs. Herein, we have investigated molecular features of the functionally important Escherichia coli topoisomerase I (EctopoI)-DNA covalent complex (EctopoIcc) for molecular simulations, which is very useful in the development of new antibacterial drugs. To demonstrate the usefulness of our approach, we used a model small molecule (SM), NSC76027, obtained from virtual screening. We examined the direct binding of NSC76027 to EctopoI as well as inhibition of EctopoI relaxation activity of this SM via experimental techniques. We then performed molecular dynamics (MD) simulations to investigate the dynamics and stability of EctopoIcc and EctopoI-NSC76027-DNA ternary complex. Our simulation results show that NSC76027 forms a stable ternary complex with EctopoIcc. EctopoI investigated here also serves as a model system for investigating a complex of topoisomerase and DNA in which DNA is covalently attached to the protein.

中文翻译：

DNA 和细菌拓扑异构酶的共价复合物：对抗菌药物开发的影响。

拓扑异构酶-DNA 瞬时共价复合物可以成为代表一类新型抗菌或抗癌药物的新型拓扑异构酶毒物抑制剂的药物靶点。在此，我们研究了功能重要的大肠杆菌拓扑异构酶 I (EctopoI)-DNA 共价复合物 (EctopoIcc) 的分子特征，用于分子模拟，这对于新型抗菌药物的开发非常有用。为了证明我们方法的实用性，我们使用了通过虚拟筛选获得的小分子 (SM) 模型 NSC76027。我们通过实验技术检查了 NSC76027 与 EctopoI 的直接结合以及该 SM 对 EctopoI 松弛活性的抑制。然后，我们进行了分子动力学 (MD) 模拟，以研究 EctopoIcc 和 EctopoI-NSC76027-DNA 三元复合物的动力学和稳定性。我们的模拟结果表明 NSC76027 与 EctopoIcc 形成稳定的三元复合物。这里研究的 EctopoI 还可以作为研究拓扑异构酶和 DNA 复合物的模型系统，其中 DNA 与蛋白质共价连接。

更新日期：2020-03-19

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