Compound for inhibiting mycobacterium tuberculosis, screening method and uses thereof

A technology of Mycobacterium tuberculosis and screening methods, applied in the field of compounds inhibiting Mycobacterium tuberculosis, its screening and application, can solve the problems of lack of crystal structure information, hindering optimization, etc., and achieve accelerated work efficiency, inhibitory activity, and large clinical Application Prospects and Effects of Potential

Inactive Publication Date: 2012-10-17
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the lack of crystal structure information for more inhibitors hampers their further optimization

Method used

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  • Compound for inhibiting mycobacterium tuberculosis, screening method and uses thereof
  • Compound for inhibiting mycobacterium tuberculosis, screening method and uses thereof
  • Compound for inhibiting mycobacterium tuberculosis, screening method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The establishment of screening model in the screening method of embodiment 1 inhibition mycobacterium tuberculosis compound

[0050] In this example, the genomic DNA of Mycobacterium tuberculosis H37Rv was extracted by phenol-chloroform extraction, and used as a template to clone the mptpb gene by PCR so that it could be expressed efficiently in E.coli BL21 (PlysS), see the attached figure 2 As shown, the mPTPB protein was purified by nickel ion affinity chromatography column, and the tyrosine phosphatase kit (RediPlate.96 Tyrosine Phosphatase Assay Kit, Molecular Probes, Inc) for enzyme activity analysis, and established a screening model targeting tyrosine phosphatase. The activity of tyrosine phosphatase at different concentrations is shown in the attached image 3 shown.

Embodiment 2

[0051] Example 2 Inhibition of the application of the screening model in the screening method of mycobacterium tuberculosis compound

[0052] 1. Inhibitor screening

[0053] Using the screening model established in Example 1 with tyrosine phosphatase as the target, the compound inhibited the activity of tyrosine phosphatase mPTPB enzyme was analyzed, and the tyrosine phosphatase kit (RediPlate.96 Tyrosine Phosphatase Assay Kit, Molecular Probes, Inc), screened 84 compounds and their derivatives isolated from marine fungi, among which 42 compounds had enzyme inhibitory activity, and the drug sensitivity test and MIC test for H37Ra found that 39 species had inhibition zone. Among them, the compound Bostrycin (see attached figure 1 shown) and its derivatives, the inhibitory enzyme activity has a strong correlation with the appearance of the inhibition zone, indicating that the target of the drug is mPTPB.

[0054] The positive control used in this embodiment to inhibit mPTPB ...

Embodiment 3

[0064] Example 3 verifies that the target of the compound Bostrycin is tyrosine phosphatase

[0065] 1. Docking analysis

[0066] Using Sybyl-x1.1 software to calculate RMSD=0.5335, the value is small, which may be closer to the actual docking situation, indicating that when Bostrycin binds to mPTPB, its positional relationship is equivalent to that of mPTPB in the 20Z5 crystal when it binds to the ligand. The average score after docking with 20Z5 using the original ligand in the 20Z5 protein crystal structure: 12.0515. The highest score after docking with Bostrycin and 20Z5 was 4.41, and the scores after docking with Bostrycin and 20Z5 were all lower than the average score after docking with the original ligand and 20Z5. It shows that the binding ability of Bostrycin to the receptor 20Z5 may be weaker than that of the original ligand. But the gap is only about 3 times. The reason may be that the original ligand has a larger spatial structure and better flexibility. The sp...

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PUM

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Abstract

The present invention discloses a screening method of a compound for inhibiting mycobacterium tuberculosis. The method comprises the following steps: (1) establishing a screening model adopting tyrosine phosphatase as a target point: adopting genome DNA of tubercle bacillus H37 Rv as a template, adopting a PCR technology to clone tyrosine phosphatase gene, transforming host cells, culturing the transformant to obtain recombinant tyrosine phosphatase from the culture, carrying out enzyme activity analysis, and establishing the screening model adopting tyrosine phosphatase as the target point; and (2) adopting the screening model established in the step (1) to screen a compound providing inhibition activity for the tyrosine phosphatase. With the method of the present invention, the tyrosine phosphatase inhibitor with anti-mycobacterium tuberculosis effect can be rapidly and efficiently screened. In addition, the present invention further discloses a compound screened by using the screening method, and uses of the compound in preparations of drugs for treatments of diseases, wherein the inducement or one of the inducements of the diseases is the tyrosine phosphatase.

Description

technical field [0001] The invention relates to a screening method for a compound inhibiting mycobacterium tuberculosis, a compound for inhibiting mycobacterium tuberculosis obtained through screening by the screening method and application of the compound. Background technique [0002] Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. According to the statistics of the World Health Organization, about 1 / 3 of the world's population is infected with tuberculosis, and there are about 8.8 million new cases and 2 million deaths due to tuberculosis every year. At present, tuberculosis treatment drugs need to be used for a long time, which is very harmful to the human body, and the infectious bacteria can remain dormant in the caseous lesions of the host for a long time and become dormant bacteria. At present, the emergence of multidrug-resistant Mycobacterium tuberculosis and the "persistence" of tuberculosis in patients have become major problems in th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N1/21C12Q1/42C12Q1/02C07C50/34A61K31/122A61P31/06A61P3/10A61P3/06A61P3/04A61P9/10A61P1/00A61P1/18A61P37/00
Inventor 陆勇军佘志刚牛长红陈洪
Owner SUN YAT SEN UNIV
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