Application of active compounds for inhibiting dimerization of DJ-1

A technology of DJ-1 and compounds, which is applied in the field of application of compounds that inhibit DJ-1 protein dimerization and the preparation of anti-tumor drugs, and can solve the problem of tumor cell inactivation, drug resistance, tumor cell mutation, etc. question

Active Publication Date: 2014-05-07
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because tumor cells are prone to mutations and drug resistance, the drug loses its activity on the mutated tumor cells.
DJ-1 is closely related to the occurrence and development of tumors, but there are still no reports on compounds or related drugs that inhibit the activity of this protein

Method used

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  • Application of active compounds for inhibiting dimerization of DJ-1
  • Application of active compounds for inhibiting dimerization of DJ-1
  • Application of active compounds for inhibiting dimerization of DJ-1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Through literature research, based on the protein crystal structure of DJ-1 (PDB ID: 1P5F, http: / / www.pdb.org), computational graphics was used to analyze and speculate the ligand-binding cavity in DJ-1. Through literature research, it was found that the Cys106 residue is critical for protein activity. DJ-1 protein is closely related to the oxidative stress of the body in vivo, and Cys106 is the most sensitive to oxidative stimulation and is the main site of activity. If the catalytic site of Cys106 can be occupied, it is possible to inhibit the activity of DJ-1. Therefore, the present invention takes the Cys106 residue of the protein as the center and searches for potential binding pockets within a range of 10° around it. Using the Amber12 molecular dynamics simulation software, dynamic simulations were performed on the selected potential binding pockets. After optimization, heating, equilibrium, etc., a total of 30ns of molecular dynamics calculations, dynamics simu...

Embodiment 2

[0076] Using the FlexE-Dock and Surflex-Dock software in the SybylX1.3 drug molecule design and simulation software package (SYBYL-X, version 1.3; Molecular Modeling Software Packages, Tripos Associates, Inc., St. Louis, MO63144, USA, 2011) , using some key amino acid interactions related to DJ-1 binding and the binding mode with potential active pockets obtained from molecular dynamics simulations, a structure-based computer-aided virtual screening of the Specs compound library was performed. Through Sybyl software's own scoring system C-Score, the docking ability of each compound in the database and DJ-1 is scored and ranked, and the top 10% compounds are selected. Then the compounds were selected according to the physical and chemical properties of the compounds such as oil-water partition coefficient (ClogP Journal of Chemical Information and Modeling 2008, 48, 465-475.) Calculate the Tanimoto value of the structural similarity coefficient of two compounds:

[0077]

...

Embodiment 3

[0102] Example 3 Compound inhibits DJ-1 dimerization experiment:

[0103] Antibodies used in the experiment were purchased from Santa Corporation (Santa Cruz, CA, USA) and Cell signaling Corporation (Cell signaling Technology); horseradish peroxidase-labeled goat anti-rabbit IgG and goat anti-mouse IgG were purchased from Calbiochem Corporation (Darmstadt, Germany); the ECL kit was purchased from Pierce (Rockford, IL, USA); the ECL plus reagent chromogenic kit was purchased from Amersham Biosciences (Arlington Heights, IL, USA).

[0104] The Western blotting method was used to determine the inhibitory effect of the 23 compounds screened on DJ-1 dimerization:

[0105] Use RIPA buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl, 1 mM EDTA, 25 mM β-glycerophosphate, 1 mM PMSF, 0.1 mM sodium vanadate, 5 μg / ml leupeptin, 1% NP40, 1% Triton X -100, 0.2%SDS) DJ-1 purified protein (4mg / mL) was diluted 1:100 times, 10μl / EP tube was aliquoted, and each compound obtained by virtual screening wa...

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Abstract

The invention provides application of active compounds in preparation of medicines for inhibiting dimerization of DJ-1. Through a computer-assisted virtualization method and technology based on a DJ-1 protein crystal structure, medicinal chemistry knowledge and pharmacological activity screening, one group of compounds for inhibiting dimerization of DJ-1 are found and the quantity of the compounds is 23. According to a principle that compounds with structure similarity coefficients Tanimoto values of more than 0.85 have similar biological activity, the molecule structure similarity Tanimoto values of more than 0.85 of the group of compounds are determined, and similar activities of inhibiting the DJ-1 are obtained. According to the application, with a DJ-1 protein relevant to the tumorigenesis development is used as a research object, compounds with functions of inhibiting the dimerization of the DJ-1 protein and inhibiting tumor cell proliferation are obtained through screening. These compounds are capable of inhibiting the dimerization of the DJ-1 protein, are strong in inhibition activity to tumor cells, and good in medicine development prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a group of compounds inhibiting the dimerization of DJ-1 protein and their application in the preparation of antitumor drugs. Background technique [0002] Cancer, also known as malignant tumor, is a disease caused by the abnormal mechanism of controlling cell growth and proliferation. In addition to growing out of control, cancer cells can also partially invade surrounding normal tissues and even transfer to other parts of the body through the internal circulatory system or lymphatic system. It not only brings great suffering to patients, but also brings heavy economic and spiritual burdens to families. [0003] DJ-1 is a protein discovered by Japanese scholar Hiroyoshi in 1997 (Daisuke Nagakubo, et al, Biochemical and Biophysical Research Communications , 1997, 213, 509-513). They isolated a new cDNA from NIH3T3 cells and obtained DJ-1 by reverse transcription. It is a dimer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/166A61K31/655A61K31/341A61K31/4704A61K31/216A61K31/415A61K31/5375A61K31/4035A61K31/4709A61K31/4155A61K31/4192A61K31/513A61K31/4196A61K31/4439A61K31/433A61K31/357A61K31/36A61P35/00
Inventor 陈建忠何俏军杨波曹戟潘有禄韩爽
Owner ZHEJIANG UNIV
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