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Discovery of small molecule inhibitors through pharmacophore modeling, molecular docking, molecular dynamics simulation and experimental validation against myeloid cell leukemia-1 (Mcl-1).

通过药效团建模、分子对接、分子动力学模拟和抗髓系细胞白血病-1 (Mcl-1) 的实验验证发现小分子抑制剂。

  • 影响因子:2.78
  • DOI:10.1080/07391102.2020.1749132
  • 作者列表:"Suleiman MR","Wang H","Huang D","Wang H","Joseph J","Huang T","Zhang F","Wang J","Cheng M
  • 发表时间:2020-03-31
Abstract

:Myeloid cell leukemia-1 (Mcl-1) protein is a family of Bcl-2 (B cell lymphoma 2) rich proteases of the most common increase threshold for genetic aberrations observed in human cancer, including lung, breast, pancreatic, cervical, and ovarian cancers as well as leukemia and lymphoma. Mcl-1 is recognized as an attractive drug target in number of diseases, including cancer. In the present study we survey and collected queries compounds from PDB database of Mcl-1 protein and generated pharmacophore-based models adapted to screen the drug-like compounds from FDA approved database. The 206 best lead molecules from pharmacophore-screening were further evaluated by molecular docking, molecular dynamics simulation, MM-GBSA calculation, as well as experimental validation. Two hits, i.e., ZINC00601272 and ZINC00002166, showed the best docking scores, which were confirmed as Mcl-1 inhibitors through biological assay in two cancer cells (HL60 and K562). Conclusively, the present study provides structural information of Mcl-1 inhibitors for next generations of cancer therapeutics through computational and experimental validation approach.

摘要

: 髓样细胞白血病-1 (Mcl-1) 蛋白是一个家族的 Bcl-2 (b细胞淋巴瘤 2) 丰富的蛋白酶的最常见的增加阈值的遗传畸变中观察到的人类癌症,包括肺,乳腺癌、胰腺癌、宫颈癌和卵巢癌以及白血病和淋巴瘤。在许多疾病中,Mcl-1 被认为是一个有吸引力的药物靶点,包括癌症。在本研究中,我们调查并收集了来自 Mcl-1 蛋白 PDB 数据库的查询化合物,并生成了基于药效团的模型,用于从 FDA 批准的数据库中筛选类药物化合物。通过分子对接、分子动力学模拟、 MM-GBSA 计算以及实验验证,进一步评价了药效团筛选的 206 个最佳铅分子。两次点击,即,ZINC00601272 和 ZINC00002166 的对接评分最好,在两种癌细胞 (HL60 和 K562) 中通过生物学检测证实为 Mcl-1 抑制剂。最后,本研究通过计算和实验验证方法为下一代癌症治疗提供了 Mcl-1 抑制剂的结构信息。

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影响因子:6.50
发表时间:2020-03-31
来源期刊:Cancer letters
DOI:10.1016/j.canlet.2019.12.039
作者列表:["Zhou Z","Zhou Q","Wu X","Xu S","Hu X","Tao X","Li B","Peng J","Li D","Shen L","Cao Y","Yang L"]

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