Revisiting Activity of Some Nocodazole Analogues as a Potential Anticancer Drugs Using Molecular Docking and DFT Calculations.
Revisiting Activity of Some Nocodazole Analogues as a Potential Anticancer Drugs Using Molecular Docking and DFT Calculations.
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DOI：
10.3389/fchem.2021.628398
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发表时间：
2021
影响因子：
5.5
通讯作者：
Al-Karmalawy AA
中科院分区：
文献类型：
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作者：
Khattab M;Al-Karmalawy AA
虽然苯并咪唑类驱虫药的潜在抗癌活性已被临床前和临床研究证实，但迄今为止尚未报道其结合相互作用的模式。因此，在这项研究中，我们的目的是提出一些苯并咪唑类驱虫剂与最重要的癌症靶点之一（微管蛋白）的结合相互作用。研究药物的选择是基于它们与微管蛋白共结晶配体（诺考达唑）的结构相似性。量子力学计算也被用于在原子和分子水平上表征所研究药物的电子构型。受试苯并咪唑类药物对微管蛋白上秋水仙碱结合位点的亲和力顺序为：氟苯达唑>奥芬达唑>诺考达唑>甲苯达唑>阿苯达唑>奥西苯达唑>芬苯达唑>环氯达唑>噻苯达唑>苯达唑。通过分析9种苯并咪唑类药物与秋水仙碱结合位点的结合方式和氢键长度，发现氟苯达唑与微管蛋白的结合效率高于其他苯并咪唑类药物。量子力学研究表明，氟苯达唑和甲苯达唑的HOMO电子密度及其MEP图与诺考达唑的HOMO电子密度及其MEP图非常相似，这也与计算的结合亲和力相一致。我们的研究对于考虑氟苯达唑作为一种有前途的抗癌候选药物的再利用具有影响。
Although potential anticancer activities of benzimidazole-based anthelmintic drugs have been approved by preclinical and clinical studies, modes of binding interactions have not been reported so far. Therefore, in this study, we aimed to propose binding interactions of some benzimidazole-based anthelmintics with one of the most important cancer targets (Tubulin protein). Studied drugs were selected based on their structural similarity with the cocrystallized ligand (Nocodazole) with tubulin protein. Quantum mechanics calculations were also employed for characterization of electronic configuration of studied drugs at the atomic and molecular level. Order of binding affinities of tested benzimidazole drugs toward colchicine binding site on tubulin protein is as follows: Flubendazole > Oxfendazole > Nocodazole > Mebendazole > Albendazole > Oxibendazole > Fenbendazole > Ciclobendazole > Thiabendazole > Bendazole. By analyzing binding mode and hydrogen bond length between the nine studied benzimidazole drugs and colchicine binding site, Flubendazole was found to bind more efficiently with tubulin protein than other benzimidazole derivatives. The quantum mechanics studies showed that the electron density of HOMO of Flubendazole and Mebendazole together with their MEP map are quite similar to that of Nocodazole which is also consistent with the calculated binding affinities. Our study has ramifications for considering the repurposing of Flubendazole as a promising anticancer candidate.