A-FABP protein inhibitor and application thereof

A technology of A-FABP and protein inhibitors, applied in the field of A-FABP protein inhibitors, can solve the problems of time-consuming and high cost, and achieve the effect of shortening the cycle and saving R&D investment

Active Publication Date: 2022-02-25
SHENZHEN INST OF ADVANCED TECH CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Traditional drug design methods are time-consuming and costly. At this time, researchers focus on computer technology, so that computer-aided drug design te

Method used

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  • A-FABP protein inhibitor and application thereof
  • A-FABP protein inhibitor and application thereof
  • A-FABP protein inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Screen out A-FABP inhibitors from the FDA drug library

[0029] Aiming at the target of A-FABP, a ligand-based naive Bayesian classification model and a structure-based molecular docking method were used to construct a virtual screening model for A-FABP ( figure 1 ).

[0030] In the DrugBank database (https: / / go.drugbank.com), the FDA-approved marketed drugs were collected, with a total of 2595 compounds for further research. A-FABP small molecule inhibitors were collected from the ChEMBL database and existing literature to define active compounds. Compounds collected from the ChEMBL database did not overlap with those in the FDA dataset. The corresponding decoys (defined as inactive) were automatically generated from the DUD-E online database (http: / / dude.docking.org / ). As shown in Table 1, the active compound data set and the inactive compound data set were randomly assigned to the training set and the test set at a ratio of 1:4. In the present inventio...

Embodiment 2

[0042] Example 2: Cell-Based Determination of A-FABP Inhibitory Activity of Candidate Compounds

[0043] The A-FABP protein of mouse and human is all 132 amino acids, and homology is 91.7%, and several key amino acid positions (Arg106, Arg126, Tyrl128) that its ligand binds in the amino acid sequence are the same, therefore, candidate compound It can be verified by inhibiting the mouse A-FABP protein.

[0044] RAW 264.7 cells (mouse mononuclear macrophage cell line) were cultured in high-glucose DMEM with 10% fetal bovine serum (FBS, Gibco, USA). The cells were divided into three groups: (1) blank control group; (2) A-FABP protein (1 μg / ml) treatment group; (3) A-FABP protein (1 μg / ml) + candidate compound treatment group. Candidate compounds were diluted to two concentrations (10 μM, 100 μM). In a 37°C, 5% CO2 incubator, the candidate compound was first incubated with the A-FABP protein for 30 minutes, and then added to the cells for 30 minutes.

[0045] Take 38g of Brewer...

Embodiment 3

[0049] Embodiment 3: the detection of candidate compound to cytotoxicity

[0050] The Cell Counting Kit-8 kit (Bioss, BA00208) was used to detect cytotoxicity, and the RAW264.6 cell culture was cultured according to the above requirements, and the experimental groups were set up: (1) blank control group (medium + CCK8 reagent, no cells) ( 2) Reagent control group (cell + medium + CCK8 reagent) (3) Solvent control group (DMSO 100 μM) (cell + medium + DMSO + CCK8 reagent) (4) A-FABP protein (1 μg / ml) treatment group ( Cell + medium + A-FBP4 protein + CCK8 reagent) (5) A-FABP protein (1 μg / ml) + candidate compound treatment group (cell + medium + A-FBP4 protein + candidate compound + CCK8 reagent), the candidate Compounds were diluted to two concentrations (10 μM, 100 μM). In a 37°C, 5% CO2 incubator, the candidate compound was first incubated with the A-FABP protein for 30 minutes, and then added to the cells for 30 minutes. Then add CCK8 reagent and treat at 37° C., 5% CO 2 f...

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Abstract

The invention discloses an A-FABP protein inhibitor and application thereof in the technical field of metabolic diseases and cardiovascular and cerebrovascular complications thereof. The active ingredient of the A-FABP protein inhibitor is cobitinib. The clinically marketed drug cobitinib is used for targeted inhibition of an A-FABP protein, and the pro-inflammatory biological activity of the A-FABP protein is inhibited by inhibiting phosphorylation of a JNK/c-Jun signal channel. The new application is developed on the basis of existing drugs, a large amount of early-stage research and development investment can be saved, meanwhile, the research and development period of the drugs is greatly shortened, and the research result provides candidate treatment drugs for various metabolic diseases.

Description

technical field [0001] The invention belongs to the technical field of metabolic diseases and cardiovascular and cerebrovascular complications thereof, and specifically relates to an A-FABP protein inhibitor and application thereof. Background technique [0002] Adipocyte-type fatty acid binding protein (A-FABP) is a member of the apolipoprotein family, with a molecular weight of 14.6KD, mainly expressed in mature adipocytes and macrophages. The main function of A-FABP protein is as a carrier of free fatty acid molecules, regulating fat storage and decomposition in adipocytes; regulating lipid accumulation and promoting the expression of various inflammatory factors in macrophages, including MCP-1, TNF-α, IL-6, IL-1β, etc. A-FABP protein can be secreted into extracellular and blood, promote inflammatory response, and is closely related to the occurrence and development of a variety of metabolic diseases, such as obesity, diabetes, lipid metabolism disorders, non-alcoholic s...

Claims

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Application Information

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IPC IPC(8): A61K31/4523C07D401/04A61P3/00A61P7/00A61P9/00A61P3/10A61P1/16A61P9/10A61P3/06G06K9/62G06N20/00G16B25/00
CPCC07D401/04A61P3/00A61P7/00A61P9/00A61P3/10A61P1/16A61P9/10A61P3/06G06N20/00G16B25/00G06F18/24155
Inventor 畅君雷杨时伦李思梦
Owner SHENZHEN INST OF ADVANCED TECH CHINESE ACAD OF SCI
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