Tao Jiang , Yunfeng Zhang , Shuihong Yu , Bingde Hu
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引用次数: 0
摘要
微卫星不稳定性(MSI)是与多种癌症相关的一个相对常见的特征,而Werner综合征(WRN)ATP依赖性螺旋酶已被认为是治疗MSI癌症(如结直肠癌)的一个新靶点。针对WRN的小分子抑制剂将是治疗高MSI表达的结直肠癌的一种有前途的策略。在这项研究中,我们采用计算机辅助药物发现策略筛选了 30,000 多个天然产物分子。通过结合使用对接、配体效率、分子力学/广义玻恩表面积(MM/GBSA)和热力学整合(TI)计算,我们发现 MOL008980、MOL010740、MOL011832、T4743、TN1166 和 TNP-002173 是潜在的 WRN 抑制剂。随后的分子动力学模拟显示,这些筛选出的天然产物具有比 ATP 底物更好的结合动态特性,能够抑制 WRN 的动态过程,是潜在的强 ATP 竞争性抑制剂。总之,我们的计算方法从天然产物数据库中发现了潜在的 WRN 抑制剂,为今后的研究提供了理论依据。
Discovering potential WRN inhibitors from natural product database through computational methods
Microsatellite instability (MSI) is a relatively common feature associated with multiple cancers, and Werner syndrome (WRN) ATP-dependent helicase has been recognized as a novel target for treating MSI cancers, such as colorectal cancer. A small-molecule inhibitor targeting WRN would be a promising strategy for treating colorectal cancer with high MSI expression. In this study, we employed a computer-assisted drug discovery strategy to screen over 30,000 natural product molecules. By using a combination of docking, ligand efficiency, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA), and thermodynamic integration (TI) calculations, we identified MOL008980, MOL010740, MOL011832, T4743, TN1166, and TNP-002173 as potential WRN inhibitors. Subsequent molecular dynamics simulation revealed that these screened natural products possessed better binding dynamic characteristics than ATP substrate and were capable of inhibiting the dynamic process of WRN, making them potential strong ATP competitive inhibitors. In conclusion, our computational approach revealed potential WRN inhibitors from a natural product database, providing a theoretical basis for future research.
期刊介绍:
The Journal of Molecular Graphics and Modelling is devoted to the publication of papers on the uses of computers in theoretical investigations of molecular structure, function, interaction, and design. The scope of the journal includes all aspects of molecular modeling and computational chemistry, including, for instance, the study of molecular shape and properties, molecular simulations, protein and polymer engineering, drug design, materials design, structure-activity and structure-property relationships, database mining, and compound library design.
As a primary research journal, JMGM seeks to bring new knowledge to the attention of our readers. As such, submissions to the journal need to not only report results, but must draw conclusions and explore implications of the work presented. Authors are strongly encouraged to bear this in mind when preparing manuscripts. Routine applications of standard modelling approaches, providing only very limited new scientific insight, will not meet our criteria for publication. Reproducibility of reported calculations is an important issue. Wherever possible, we urge authors to enhance their papers with Supplementary Data, for example, in QSAR studies machine-readable versions of molecular datasets or in the development of new force-field parameters versions of the topology and force field parameter files. Routine applications of existing methods that do not lead to genuinely new insight will not be considered.