Identification of a novel class of small compounds with anti-tuberculosis activity by in silico structure-based drug screening

Taira Junichi; Morita Koji; Kawashima Shotaro; Umei Tomohiro; Baba Hiroki; Maruoka Taira; Komatsu Hideyuki; Sakamoto Hiroshi; Sacchettini James C.; Aoki Shunsuke

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Identification of a novel class of small compounds with anti-tuberculosis activity by in silico structure-based drug screening

机译：在基于硅结构的药物筛选中鉴定抗结核活性的小型化合物

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The enzymes responsible for biotin biosynthesis in mycobacteria have been considered as potential drug targets owing to the important role in infection and cell survival that the biotin synthetic pathway plays in Mycobacterium tuberculosis. Among the enzymes that comprise mycobacterium biotin biosynthesis systems, 7,8-diaminopelargonic acid synthase (DAPAS) plays an essential role during the stationary phase in bacterial growth. In this study, compounds that inhibit mycobacterial DAPAS were screened in the virtual chemical library using an in silico structure-based drug screening (SBDS) technique, and the antimycobacterial activity of the selected compounds was validated experimentally. The DOCK-GOLD programs utilized by in silico SBDS facilitated the identification of a compound, referred to as KMD6, with potent inhibitory effects on the growth of model mycobacteria (M. smegmatis). The subsequent compound search, which was based on the structural features of KMD6, resulted in identification of three additional active compounds, designated as KMDs3, KMDs9 and KMDs10. The inhibitory effect of these compounds was comparable to that of isoniazid, which is a first-line antituberculosis drug. The high antimycobacterial activity of KMD6, KMDs9 and KMDs10 was maintained on the experiment with M. tuberculosis. Of the active compounds identified, KMDs9 would be a promising pharmacophore, owing to its long-term antimycobacterial effect and lack of cytotoxicity.

机译：由于生物素合成途径在结核分枝杆菌中发挥的感染和细胞存活中，潜在的药物靶标，该酶被认为是潜在的药物靶标。在含有分枝杆菌生物素生物合成体系的酶中，7,8-二氨基氨基酸合酶（DAPAs）在细菌生长的固定相期间起着重要作用。在该研究中，使用基于硅结构的药物筛选（SBDs）技术在虚拟化学文库中筛选抑制分枝杆菌DAPA的化合物，并通过基于硅结构的药物筛选（SBDs）技术进行抗致细胞活性。在硅SBD中使用的码头 - 黄金计划促进了称为KMD6的化合物，对模型分枝杆菌（Smogmatis）的生长有效的抑制作用。随后的化合物搜索，其基于KMD6的结构特征，导致鉴定三种另外的活性化合物，称为KMDS3，KMDS9和KMD10。这些化合物的抑制作用与异烟肼的抑制作用相当，这是一种第一线抗核酸药物。 KMD6，KMDS9和KMDS10的高抗细细菌活性得到了对肺结核的实验。在鉴定的活性化合物中，KMDS9将是一个有前途的药疗法，由于其长期抗致症效应和缺乏细胞毒性。

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来源
《The Journal of Antibiotics: An International Journal》 |2017年第11期|共8页
作者
Taira Junichi; Morita Koji; Kawashima Shotaro; Umei Tomohiro; Baba Hiroki; Maruoka Taira; Komatsu Hideyuki; Sakamoto Hiroshi; Sacchettini James C.; Aoki Shunsuke;
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作者单位

Kyushu Inst Technol Grad Sch Comp Sci &

Syst Engn Dept Biosci &

Bioinformat Iizuka Fukuoka;

Kyushu Inst Technol Grad Sch Comp Sci &

Syst Engn Dept Biosci &

Bioinformat Iizuka Fukuoka;

Kyushu Inst Technol Grad Sch Comp Sci &

Syst Engn Dept Biosci &

Bioinformat Iizuka Fukuoka;

Kyushu Inst Technol Grad Sch Comp Sci &

Syst Engn Dept Biosci &

Bioinformat Iizuka Fukuoka;

Kyushu Inst Technol Grad Sch Comp Sci &

Syst Engn Dept Biosci &

Bioinformat Iizuka Fukuoka;

Kyushu Inst Technol Grad Sch Comp Sci &

Syst Engn Dept Biosci &

Bioinformat Iizuka Fukuoka;

Kyushu Inst Technol Grad Sch Comp Sci &

Syst Engn Dept Biosci &

Bioinformat Iizuka Fukuoka;

Kyushu Inst Technol Grad Sch Comp Sci &

Syst Engn Dept Biosci &

Bioinformat Iizuka Fukuoka;

Texas A&

M Univ Dept Biochem &

Biophys College Stn TX 77843 USA;

Kyushu Inst Technol Grad Sch Comp Sci &

Syst Engn Dept Biosci &

Bioinformat Iizuka Fukuoka;

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正文语种 eng
中图分类药学;
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1. Identification of a novel class of small compounds with anti-tuberculosis activity by in silico structure-based drug screening [J] . Taira Junichi, Morita Koji, Kawashima Shotaro, The Journal of Antibiotics: An International Journal . 2017,第11期

机译：在基于硅结构的药物筛选中鉴定抗结核活性的小型化合物
2. Post Processing of Protein-Compound Docking for Fragment-Based Drug Discovery (FBDD): In-Silico Structure-Based Drug Screening and Ligand-Binding Pose Prediction [J] . Jerry O. Ebalunode Weifan Zheng Current Topics in Medicinal Chemistry . 2010,第06期

机译：用于基于片段的药物发现（FBDD）的蛋白复合物对接的后处理：基于硅结构的药物筛选和配体结合姿势预测
3. Identification of compounds with potential antibacterial activity against Mycobacterium through structure-based drug screening [J] . Kinjo T., Koseki Y., Kobayashi M., Journal of chemical information and modeling . 2013,第5期

机译：通过基于结构的药物筛选鉴定对分枝杆菌具有潜在抗菌活性的化合物
4. Structure-based Drug Screening and Ligand-Based Drug Screening Toward Protein-Compound Network [C] . Yoshifumi Fukunishi International Conference of Computational Methods in Sciences and Engineering 2007(ICCMSE 2007); 20070925-30; Corfu(GR) . 2007

机译：面向蛋白质复合网络的基于结构的药物筛选和基于配体的药物筛选
5. Screening potato genotypes for antioxidant activity, identification of the responsible compounds, and differentiating Russet Norkotah strains using AFLP and microsatellite marker analysis. [D] . Hale, Anna Louise. 2003

机译：使用AFLP和微卫星标记分析法筛选马铃薯基因型的抗氧化活性，鉴定负责的化合物并区分Russet Norkotah菌株。
6. Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach [O] . Shweta Choudhary, Yashpal S. Malik, Shailly Tomar 2020

机译：用基于硅结构的虚拟筛选方法的药物重新扫描鉴定SARS-COV-2细胞入口抑制剂
7. Identification of new benzamide inhibitor against α-subunit of tryptophan synthase from Mycobacterium tuberculosis through structure-based virtual screening, anti-tuberculosis activity and molecular dynamics simulations [O] . Sadia Naz, Umar Farooq, Sajid Ali, 2018

机译：基于结构的虚拟筛选，抗结核活动和分子动力学模拟从结核分枝杆菌中抗黄球合酶α-亚基α - 亚基β-亚基抑制剂的鉴定

Identification of a novel class of small compounds with anti-tuberculosis activity by in silico structure-based drug screening

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