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Application of quinacrine in preparation of medicine for treating pulmonary fibrosis

A pulmonary fibrosis and drug technology, applied in the field of chemical drug development, can solve the problem of lack of specific and effective treatment methods, and achieve the effect of broadening the scope of application

Active Publication Date: 2021-12-03
JINAN CENTER HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] It can be seen that pulmonary fibrosis is a serious threat to human health, but its exact pathogenesis has not yet been fully understood, and there is still a lack of specific and effective treatments. Therefore, research on the pathogenesis of pulmonary fibrosis has guiding significance for clinical treatment.

Method used

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  • Application of quinacrine in preparation of medicine for treating pulmonary fibrosis
  • Application of quinacrine in preparation of medicine for treating pulmonary fibrosis
  • Application of quinacrine in preparation of medicine for treating pulmonary fibrosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Surface Plasmon Resonance Technology Experiment (Surface Plasmon Resonance SPR Experiment)

[0041] 1) Sample information

[0042] Stationary Phase:

[0043] name molecular weight Buffer concentration CUL4B 130.4 KD Tris 30 μg / mL

[0044] mobile phase:

[0045] name molecular weight Buffer (quinacrine hydrochloride content) quinacrine hydrochloride 472.88 65mg

[0046] 2) Instrument parameters

[0047] Protein immobilization: Instrument: Biacore S200; chip type: S-CM5; Running buffer: PBS-P; Ligand concentration: 30 μg / mL; flow rate: 10 μL / min. Regeneration conditions: regeneration solution: 10 mM glycine-HCl, pH 2.0; injection time: 30 s; flow rate: 30 μL / min. Kinetic analysis: Control channel: flow cell 1; Running buffer: PBSP, 2%DMSO; Contact time: 120 s; Dissociation time: 300 s; Flow rate: 30 μL / min;

[0048] 3) Experimental process

[0049] Sample dissolution and dilution:

[0050] 3.1) Liquid exchange...

Embodiment 2

[0075] Computer Simulation Molecular Docking Experiment (MOE-Dock Experiment)

[0076] MOE Dock was used for molecular docking of quinacrine hydrochloride and CUL4B. The 2D structure of quinacrine was downloaded from PubChem and converted to a 3D structure in MOE by energy minimization as a ligand. The crystal structure of CUL4B was downloaded from the RCSB protein database (http: / / www.rcsb.org / ), PDB ID is 4A0C2. The C chain of 4A0C is used as the pair acceptor. Before docking, AMBER10: Implicit solvation model of force field and reaction field (r-field) of EHT was selected. Select the "Induced Fit" scheme to allow the receptor binding site side chains to move according to the ligand conformation and impose constraints on their position. The weight used to tie the side chain atoms to their original positions was 10. First, the London dG scoring function is used to score all docking poses, and then the force field refinement is performed on the first 30 poses, and then the...

Embodiment 3

[0081] Drug (quinacrine) and target protein (CUL4B) binding stability test (DARTS test)

[0082] 1) Plasmid construction and transfection: Plasmid construction is the most commonly used experimental technique in molecular biology research. The principle relies on the action of restriction endonuclease, DNA ligase and other modifying enzymes. After appropriate cutting and modification of the target gene and carrier DNA, the two are connected together and then introduced into the host cell to realize the target gene in the host cell. Correct expression in host cells. Plasmids containing different CUL4B protein domains with FLAG tags were constructed respectively, and the constructed plasmids were respectively transfected into tool cell 293T cells and then incubated at 37°C and 5% CO 2 and cultured in an incubator with saturated humidity for 48 h.

[0083] 2) Prepare DARTS cell lysate (1 mL): M-PER mammalian protein extraction reagent 730 μL, protease inhibitor 10 μL, 200 mM ph...

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Abstract

The invention relates to application of quinacrine in preparation of a medicine for treating pulmonary fibrosis. A structural formula of the quinacrine is shown in the specification. According to the application, it is found for the first time that the quinacrine can be used for inhibiting Smad2 / 3 phosphorylation through targeting a CUL4B protein, then, a TGF-beta1 / Smads signal transduction pathway is affected, the effect of treating the pulmonary fibrosis is achieved, and the defect that in the prior art, the quinacrine only serves as a sensitizer to participate in a treatment process of cancers such as liver cancer are overcome, so that the application range of the quinacrine is obviously widened.

Description

technical field [0001] The invention relates to the application of quinacrine in the preparation of medicines for treating pulmonary fibrosis, and belongs to the technical field of chemical medicine development. Background technique [0002] Pulmonary fibrosis is a group of interstitial lung diseases characterized by progressive dyspnea, cough, gas exchange disorder and respiratory failure caused by multiple etiologies. It is characterized by the proliferation and differentiation of fibroblasts residing in the pulmonary interstitium and around blood vessels into myofibroblasts and the generation of excess extracellular matrix (ECM) that is deposited in the alveoli and pulmonary interstitium. Studies have found that the key pathway of extracellular matrix (ECM) production is related to TGF-β1 / Smads signal transduction. [0003] In the process of pulmonary fibrosis, the joint influence of various factors, especially the stimulation of a large number of cytokines, will make lu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/473A61K9/00A61P11/00
CPCA61K31/473A61K9/007A61P11/00
Inventor 宁斌金政鑫刘镕菡董辉张英田立歌朱苹
Owner JINAN CENTER HOSPITAL
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