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Use of active compounds that inhibit dj-1 dimerization

A technology of DJ-1 and compound, which is applied to the compound that inhibits the dimerization of DJ-1 protein, and the application field in the preparation of anti-tumor drugs, which can solve the inactivation of tumor cells, the generation of drug resistance, the easy mutation of tumor cells, etc. question

Active Publication Date: 2016-01-20
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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  • Use of active compounds that inhibit dj-1 dimerization
  • Use of active compounds that inhibit dj-1 dimerization
  • Use of active compounds that inhibit dj-1 dimerization

Examples

Experimental program
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Effect test

Embodiment 1

[0074] Through literature research, based on the protein crystal structure of DJ-1 (PDBID: 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, kinetic simulations were performed on the selected potential binding pockets. After optimization, heating, equilibrium, etc., a total of 30ns of molecular dynamics calculations, dynamics simul...

Embodiment 2

[0076]Using the FlexE-Dock and Surflex-Dock software in the SybylX1.3 drug molecule design and simulation software package (SYBYL-X, version1.3; Molecular Modeling Software Packages, Tripos Associates, Inc., St. Louis, MO63144, USA, 2011), the molecular The interaction of some key amino acids related to the binding of DJ-1 and the binding mode with the potential active pocket obtained from the kinetic simulation were used for structure-based computer-aided virtual screening of the Specs compound library. 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:

[0...

Embodiment 3

[0102] Example 3 Compounds inhibiting the dimerization of DJ-1:

[0103] The antibodies used in the experiment were purchased from Santa Company (Santa Cruz, CA, USA) and Cell Signaling Company (Cell Signaling Technology); horseradish peroxidase-labeled goat anti-rabbit IgG and goat anti-mouse IgG were purchased from Calbiochem Company (Darmstadt, Germany); ECL Kits were purchased from Pierce Company (Rockford, IL, USA); ECLplus Reagent Chromogenic Kit was purchased from Amersham Biosciences Company (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] Purified DJ-1 protein using RIPA buffer (50mM Tris-HCl pH7.4, 150mM NaCl, 1mM EDTA, 25mM β-glycerophosphate, 1mMPMSF, 0.1mM sodium vanadate, 5μg / mlleupeptin, 1%NP40, 1%TritonX-100, 0.2%SDS) (4mg / mL) was diluted 1:100 times, 10μl / EP tube was aliquoted, and each compound obtained by virtual screening was added se...

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Abstract

The invention provides the application of a group of active compounds in the preparation of drugs for inhibiting DJ-1 dimerization. A group of 23 compounds that inhibit DJ-1 dimerization were discovered through computer-aided virtual methods and techniques based on DJ-1 protein crystal structure, medicinal chemistry knowledge, and pharmacological activity screening. According to the compounds whose structural similarity coefficient Tanimoto value is greater than 0.85, have similar biological activity principles, it is determined that the molecular structural similarity Tanimoto value of this group of compounds is greater than 0.85, and also have similar inhibitory DJ-1 activity. The invention takes the DJ-1 protein related to the occurrence and development of tumor as the research object, and screens to obtain the compound capable of inhibiting the dimerization of the DJ-1 protein and inhibiting the proliferation of tumor cells. These compounds can not only inhibit the dimerization of DJ-1 protein, but also have strong inhibitory activity on tumor cells, and have good prospects for drug development.

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 Patents(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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