调查抗生素作为拓扑异构酶II抑制剂和DNA插入剂的潜在抗癌活性：体外、分子对接、分子动力学和SAR研究。
Investigating the potential anticancer activities of antibiotics as topoisomerase II inhibitors and DNA intercalators: in vitro, molecular docking, molecular dynamics, and SAR studies.
发表日期：2023 Dec
作者：
Faten Farouk, Ayman Abo Elmaaty, Ahmed Elkamhawy, Haytham O Tawfik, Radwan Alnajjar, Mohammed A S Abourehab, Mohamed A Saleh, Wagdy M Eldehna, Ahmed A Al-Karmalawy
来源：
J Enzym Inhib Med Ch
摘要：
Topoisomerase II (TOP-2) 是一种有前途的癌症治疗分子靶点。许多抗生素可以与生物相关的大分子进行相互作用，并引发抗肿瘤潜力。本文采用分子对接研究，对138种抗生素与人类拓扑异构酶II-DNA复合物的结合相互作用进行了调查，接着进行了200 ns 的分子动力学模拟和MM-GBSA计算。另一方面，选取最有前途的候选药物，以多柔比星（DOX）为参考药物，对三种癌症细胞系的抗肿瘤活性进行了研究。值得注意的是，螺旋霉素（SP）和克拉霉素（CL）显示出在MCF-7细胞系中有良好的抗癌潜力。此外，阿奇霉素（AZ）和CL表现出良好的抗癌潜力，可以应用于HCT-116细胞系。最后进行了TOP-2酶抑制实验，以证实所提出的理论依据。简而言之，对于红霉素（ER）和罗红霉素（RO），记录了强效的TOP-2抑制潜力。此外，一项SAR研究揭示出这些抗生素遇到的有前途的抗癌药物成分。重点研究内容包括： 将139种抗生素与拓扑异构酶II-DNA复合物进行分子对接研究；SP、RO、AZ、CL和ER是最有前途和市售的候选物；对五个最有前途的复合物进行了200 ns的分子动力学模拟；对前五个复合物进行了 MM-GBSA 计算；SP和CL在 MCF-7 细胞系中显示出有良好的抗癌潜力，此外 AZ 和 CL 也在HCT-116细胞系中表现出良好的抗癌潜力；ER和RO记录下了强效的TOP-2抑制潜力。
Topoisomerase II (TOP-2) is a promising molecular target for cancer therapy. Numerous antibiotics could interact with biologically relevant macromolecules and provoke antitumor potential. Herein, molecular docking studies were used to investigate the binding interactions of 138 antibiotics against the human topoisomerase II-DNA complex. Followed by the MD simulations for 200 ns and MM-GBSA calculations. On the other hand, the antitumor activities of the most promising candidates were investigated against three cancer cell lines using doxorubicin (DOX) as a reference drug. Notably, spiramycin (SP) and clarithromycin (CL) showed promising anticancer potentials on the MCF-7 cell line. Moreover, azithromycin (AZ) and CL exhibited good anticancer potentials against the HCT-116 cell line. Finally, the TOP-2 enzyme inhibition assay was carried out to confirm the proposed rationale. Briefly, potent TOP-2 inhibitory potentials were recorded for erythromycin (ER) and roxithromycin (RO). Additionally, a SAR study opened eyes to promising anticancer pharmacophores encountered by these antibiotics.HighlightsMolecular docking studies of 139 antibiotics against the topoisomerase II-DNA complex.SP, RO, AZ, CL, and ER were the most promising and commercially available candidates.Molecular dynamics simulations for 200 ns for the most promising five complexes.MM-GBSA calculations for the frontier five complexes.SP and CL showed promising anticancer potentials on the MCF-7 cell line, besides, AZ and CL exhibited good anticancer potentials against the HCT-116 cell line.Potent TOP-2 inhibitory potentials were recorded for ER and RO.