新型异芳基氨基-3-芳基-1H-吲唑类蛋白激酶CK2抑制剂的体外活性评价及SAR研究

Q4 Biochemistry, Genetics and Molecular Biology
M. Protopopov, V. Vdovin, S. S. Lukashov, O. V. Ostrynska, I. Borysenko, O. Borovykov, S. Starosyla, Y. Bilokin, O. P. Kukharenko, V. Bdzhola, S. Yarmoluk
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引用次数: 0

摘要

目标在5-甲氨基-1H-吲唑中鉴定新的蛋白激酶CK2抑制剂。方法。γ-32P ATP体外激酶测定法进行生化检测。通过Autodock 4.2.6程序包执行分子对接,使用DrugScore评分功能重新存储对接结果。后果在17种研究的5-氨基-3-芳基林达唑衍生物中,鉴定出11种IC50在纳摩尔范围内的蛋白激酶CK2抑制剂。最具活性的化合物具有IC50=2nM。SAR研究和这些化合物的附加分子模型使我们能够选择潜在的取代基来构建具有改进的活性和物理化学性质的新化合物。结论。作为这项工作的结果,开发了11种纳摩尔蛋白激酶CK2抑制剂,并使用分子对接方法提出了这些化合物与ATP受体位点的结合模式。分析了所研究化合物的理化性质和取代基的SAR,并设计了6个新化合物作为蛋白激酶CK2抑制剂进行进一步开发。综上所述,5-己基氨基-1H-吲唑类化合物是进一步开发CK2抑制剂的良好基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Evaluation of in vitro activity and SAR study of the novel hetarylamino-3-aryl-1H-indazole derivatives as inhibitors of protein kinase CK2
Aim. To identify novel protein kinase CK2 inhibitors among the 5-hetarylamino-1H-indazoles. Methods. Biochemical testing was carried out with the aid of γ- 32 P ATP in vitro kinase assay. Molecular docking via the Autodock 4.2.6 program package was executed, rescoring of docking results was performed using DrugScore scoring function. Results. Among the 17 studied 5-amino-3-arylindazole derivatives 11 inhibitors of protein kinase CK2 with IC 50 in nanomolar range were identified. The most active compound has IC 50 = 2 nM. SAR study and addi-tional molecular modeling of these compounds allowed us to select prospective substituents for construction of novel compounds with improved activity and physicochemical properties. Conclusions. As a result of this work 11 nanomolar protein kinase CK2 inhibitors were de-veloped and the binding modes of these compounds with the ATP-acceptor site were proposed using molecular docking methods. The physicochemical properties and SAR of substituents of studied compounds were analyzed and 6 novel compounds were designed for further development as protein kinase CK2 inhibitors. Summarizing, 5-heterylamino-1H-indazoles are a good basis for further CK2 inhibitors development.
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来源期刊
Biopolymers and Cell
Biopolymers and Cell Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
1.10
自引率
0.00%
发文量
9
期刊介绍: “Biopolymer and cell” is published since 1985 at the Institute of Molecular Biology and Genetics NAS of Ukraine under the supervision of the National Academy of Sciences of Ukraine. Our journal covers a wide scope of problems related to molecular biology and genetics including structural and functional genomics, transcriptomics, proteomics, bioinformatics, biomedicine, molecular enzymology, molecular virology and immunology, theoretical bases of biotechnology, physics and physical chemistry of proteins and nucleic acids and bioorganic chemistry.
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