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Application of PPD in preparation of drugs for preventing or treating TGF beta pathway related diseases

A technology for use and disease, applied in the field of medicine and chemistry, to achieve the effect of treating diseases related to TGFβ pathway

Inactive Publication Date: 2021-08-31
INST OF ZOOLOGY CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the study found that 20S-protopanaxadiol saponin has a wide range of biological activities, it still needs to be further studied in order to make it better used in the field of medicine

Method used

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  • Application of PPD in preparation of drugs for preventing or treating TGF beta pathway related diseases
  • Application of PPD in preparation of drugs for preventing or treating TGF beta pathway related diseases
  • Application of PPD in preparation of drugs for preventing or treating TGF beta pathway related diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 Effect of PPD on protein stability of MBP, TGFβR1, and TGFβR2

[0044] In this application, in order to determine the stability of PPD binding to TGFβR1, TGFβR2 and MBP, the following experiments were carried out:

[0045] Mix 1mg / ml protein (TGFβR1, TGFβR2, MBP) with 400μM PPD (Jilin Mengchuang Biotechnology Co., Ltd., GR0515, the same below), and place it overnight at 4°C. Set up a protein control group without PPD, 2 for each group. Repeat, use the Prometheus NT.48 instrument (Germany nanotemper company) to measure the protein melting temperature Tm value, the principle of this instrument is to measure the change of the ratio of protein absorption at 350nm and absorption at 330nm at different temperatures, because tryptophan has fluorescence absorption at 350nm , tryptophan is a hydrophobic amino acid. When the protein structure is stable, tryptophan is located inside the protein, and the ratio of 350nm fluorescence absorption to 330nm fluorescence absorpti...

Embodiment 2

[0046] Example 2 Binding affinity of PPD to TGFβR1, TGFβR2 and MBP

[0047] In order to further measure the affinity of PPD with MBP, TGFβR1 and TGFβR2, we use the MST-nanotemper instrument (Germany nanotemper company), the steps are as follows:

[0048] 100 μL of 10 μM / L proteins (TGFβR1, TGFβR2, MBP) were labeled with fluorescent dyes respectively, PPD was diluted twice from 400 μM / L gradient, mixed with different concentrations of PPD and fluorescent dye-labeled proteins, and tested on the machine. The principle of the instrument is The sample is heated by an infrared laser to generate a microscopic temperature gradient field, and then the directional movement of the molecule is detected and quantified by a covalently bound fluorescent dye, so as to obtain the binding behavior of the PPD-protein. The results are as follows figure 1 , The dissociation constant Kd of PPD and TGFβR1 is 1.54μM, and PPD does not combine with MBP and TGFβR2.

Embodiment 3

[0049] Example 3 Kinetic simulation of PPD and TGFβR1 complex

[0050]In this application, in order to obtain the specific binding mode of PPD and TGFβR1, use AUTODOCK vina small molecule-protein (version 1.1.2, http: / / vina.scripps.edu / ) docking software, and GROMACS (version 2020.5, http: / / vina.scripps.edu / ) complex simulation software, first use AUTODOCK vina to dock PPD and TGFβR1 ectodomain structure to obtain the structure of TGFβR1-PPD complex, then use GROMACS 2020.5 software, use Charmm36-mar2019 force field, TGFβR1 -PPD is placed in a twelve-square box, TIP3P water molecules are added, the system neutralizes the charge with Na+ and Cl-, the NaCl concentration of the aqueous solution of the system is set to 0.15M (that is, the concentration of normal saline), and the energy is minimized first, so that the maximum energy of the system is less than 1000kJ / mol / nm, followed by a two-step equilibrium of the system to stabilize the temperature of the system at 300K and the ...

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Abstract

The invention provides application of 20S-protopanaxadiol saponin or pharmaceutically acceptable salt, isomer, solvate, prodrug or derivative thereof in inhibition of TGF beta pathway, wherein the 20S-protopanaxadiol saponin or pharmaceutically acceptable salt, isomer, solvate, prodrug or derivative thereof is bound to the extracellular domain of TGF beta R1, and the binding sites include D57, P59, P64 and N78. The invention also provides application of 20S-protopanaxadiol saponin or pharmaceutically acceptable salt, isomer, solvate, prodrug or derivative thereof in preparation of drugs for preventing and / or treating TGF beta pathway related diseases, and the effect of treating diseases is achieved by blocking the TGF beta pathway. The application has important significance for prevention and treatment of TGF beta pathway related diseases in the future, and is expected to produce considerable social and economic benefits.

Description

technical field [0001] This application relates to the field of medicinal chemistry, and relates to a new application of a compound, especially to the application of 20S-protopanaxadiol saponin to inhibit diseases related to TGFβ pathway, wherein the 20S-protopanaxadiol saponin or its pharmaceutically acceptable salt , isomers, solvates, prodrugs or derivatives bind to binding sites D57, P59, P64, N78 on the extracellular domain of TGFβR1. Background technique [0002] The transforming growth factor β (transforming growth factor β, TGFβ) signaling pathway is mainly involved in mediating the normal growth and development of tissues and organs, the body's immune response and other biological processes by regulating cell growth, proliferation, differentiation, migration and apoptosis. process. The TGFβ pathway is related to liver, lung, and kidney fibrosis. The TGFβ pathway induces the activation of stellate cells, the secretion of fibrin, and the fibrosis continues to lead to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7032A61P35/00A61P37/06A61P19/08A61P43/00A23L33/11
CPCA61K31/7032A61P35/00A61P37/06A61P19/08A61P43/00A23L33/11A23V2002/00A61K36/258A23V2200/30A23V2200/306A23V2200/308A23V2200/324A23V2250/21368
Inventor 金万洙
Owner INST OF ZOOLOGY CHINESE ACAD OF SCI
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