基于结构和片段的设计、对接和分子动力学模拟研究,设计2-氨基-6-甲基嘧啶苯甲酸作为ATP竞争性酪蛋白激酶-2 (CK2)抑制剂。

IF 2.3 3区 环境科学与生态学 Q3 CHEMISTRY, MULTIDISCIPLINARY
S Patel, S Patel, K Tulsian, P Kumar, V K Vyas, M Ghate
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引用次数: 1

摘要

酪蛋白激酶-2 (CK2)的过表达与多种癌症有关,主要是肺癌、前列腺癌和急性髓性白血病。与相关激酶相比,较小的核苷酸袋为发现新的atp竞争性CK2抑制剂提供了很好的机会。在这项研究中,我们采用了基于集成结构和片段的设计策略来设计2-氨基-6-甲基嘧啶苯甲酸作为atp竞争性CK2抑制剂。基于四个特征的e -药效团(ARRR)模型筛选了780,092个分子。此外,检索到的hit被考虑用于分子对接研究,以确定基本的结合相互作用。同时,使用1,542,397个片段的数据集进行基于片段的虚拟筛选。以鉴定出的片段和片段为结构模板,设计了新型CK2抑制剂- 2-氨基-6-甲基嘧啶苯甲酸。最后,通过诱导拟合对接(IFD)研究确定了设计命中的结合相互作用,并通过100 ns的分子动力学(MD)模拟研究估计了它们的稳定性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Design of 2-amino-6-methyl-pyrimidine benzoic acids as ATP competitive casein kinase-2 (CK2) inhibitors using structure- and fragment-based design, docking and molecular dynamic simulation studies.

Overexpression of casein kinase-2 (CK2) has been implicated in several carcinomas, mainly lung, prostate and acute myeloid leukaemia. The smaller nucleotide pocket compared to related kinases provides a great opportunity to discover newer ATP-competitive CK2 inhibitors. In this study, we have employed an integrated structure- and fragment-based design strategy to design 2-amino-6-methyl-pyrimidine benzoic acids as ATP-competitive CK2 inhibitors. A statistically significant four features-based E-pharmacophore (ARRR) model was used to screen 780,092 molecules. Further, the retrieved hits were considered for molecular docking study to identify essential binding interactions. At the same time, fragment-based virtual screening was performed using a dataset of 1,542,397 fragments. The identified hits and fragments were used as structure templates to rationalize the design of 2-amino-6-methyl-pyrimidine benzoic acids as newer CK2 inhibitors. Finally, the binding interactions of the designed hits were identified using an induced fit docking (IFD) study, and their stability was estimated by a molecular dynamics (MD) simulation study of 100 ns.

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来源期刊
CiteScore
5.20
自引率
20.00%
发文量
78
审稿时长
>24 weeks
期刊介绍: SAR and QSAR in Environmental Research is an international journal welcoming papers on the fundamental and practical aspects of the structure-activity and structure-property relationships in the fields of environmental science, agrochemistry, toxicology, pharmacology and applied chemistry. A unique aspect of the journal is the focus on emerging techniques for the building of SAR and QSAR models in these widely varying fields. The scope of the journal includes, but is not limited to, the topics of topological and physicochemical descriptors, mathematical, statistical and graphical methods for data analysis, computer methods and programs, original applications and comparative studies. In addition to primary scientific papers, the journal contains reviews of books and software and news of conferences. Special issues on topics of current and widespread interest to the SAR and QSAR community will be published from time to time.
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