Method for virtually screening cholesterol degrading medicine with 24-dehydrocholesterol reductase (DHCR24) being target point

A DHCR24, dehydrocholesterol technology, applied in special data processing applications, instruments, electrical digital data processing, etc., can solve the problems of high cost and less than 10% success rate, and achieve the effect of improving efficiency and shortening the research and development cycle.

Active Publication Date: 2017-06-30
LIAONING UNIVERSITY
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AI Technical Summary

Problems solved by technology

The research and development of new drugs generally takes more than 10 years from the establishment

Method used

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  • Method for virtually screening cholesterol degrading medicine with 24-dehydrocholesterol reductase (DHCR24) being target point
  • Method for virtually screening cholesterol degrading medicine with 24-dehydrocholesterol reductase (DHCR24) being target point
  • Method for virtually screening cholesterol degrading medicine with 24-dehydrocholesterol reductase (DHCR24) being target point

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 A virtual screening method for cholesterol-lowering drugs targeting 24-dehydrocholesterol reductase

[0042] Proceed as follows:

[0043] (1) Establishment of the catalytic activity pocket of DHCR24 enzyme

[0044] 1. Download the amino acid sequence of DHCR24 protein on UniProt ( figure 1 ), and its three-dimensional structure was obtained by homology modeling. Predict protein structures on the I-TASSER Server online server. Using the scoring software LGscore (>1.5correct model) scoring result is 2.53, Maxsub (>0.1correct model) scoring result is 0.17, VERIFY3D (>80% of the residues had an averaged 3D-1D score>=0.2) scoring result is 82.79 %, the scoring result of Ramachandran plot (favoured and allowed region>90%) was 95%, and the structural model with higher scoring was finally determined as the three-dimensional structural model of DHCR24 protein ( figure 2 ).

[0045] 2. Pretreatment of the macromolecule receptor DHCR24. Process the higher-scoring ...

Embodiment 2

[0055] Example 2 Preliminary confirmation of the cholesterol-lowering efficacy of candidate drugs at the cellular level.

[0056] In order to further confirm the cholesterol-lowering efficacy of small molecule drug candidates obtained through virtual screening, two drugs, Conivaptan (DB00872) and Risperidone (DB00734), were verified at the cellular level. Firstly, hepG2 cells (human liver cancer cells) were cultured, and the optimal concentration of each drug was obtained according to the literature and experimental observations, and a complete medium (S+), a serum-free and antibiotic-free medium (S(-)), and a blank control group were set. , U18666a (known DHCR24 inhibitor, positive control group, the concentration is 2μM) and two drug groups (Conivaptan is 5μM, Risperidone is 1μM), 24 hours after administration, the cell pellet was collected to extract the total lipid, and the high-efficiency liquid phase determination. First use cholesterol (cholesterol) and cholesterol (de...

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Abstract

The invention relates to a method for virtually screening cholesterol degrading medicine with 24-dehydrocholesterol reductase (DHCR24) being a target point. The method includes the steps that 1, the molecular structure of DHCR24 is determined; 2, molecular docking software is adopted, the active center of macromolecular docking of the medicine is determined according to a combined pocket which is formed after desmosterol and DHCR24 are docked, and an active pocket is set; 3, a macromolecular ligand databse used for docking is arranged; 4, according to the set active pocket, by the utilization of the molecular docking software, macromolecular ligands in the macromolecular ligand database used for docking and the active pocket are docked in sequence; 5, results which are screened after primary docking are accurately docked, and the candidate medicine having the effect of cholesterol degrading are determined. By the adoption of the method, within short time, the macromolecular candidate medicine which has the effect of competitive restraining of DHCR24 and is developed into the novel cholesterol degrading medicine is obtained, in this way, the research and development efficiency is greatly improved, and the research period of new medicine is shortened.

Description

technical field [0001] The present invention relates to a drug screening method, especially taking 24-dehydrocholesterol reductase (3β-dehydrocholesterol-Δ24 reductase, 3β-hydroxysterolΔ-24-reductase, DHCR24) as the target, and using molecular docking software to detect small molecules A method for virtual screening of cholesterol-lowering drugs against databases. Background technique [0002] Cholesterol is an indispensable and important substance for human tissue cells, but excessive cholesterol levels can induce diseases, especially cardiovascular diseases. May 2016 is my country's first "Cholesterol Month". According to the latest data from the "China Cardiovascular Disease Report 2014", there are about 290 million patients with cardiovascular disease in my country, and the prevalence rate is still rising. The rising trend of cardiovascular disease mortality in my country is mainly due to the rise of ischemic heart disease death caused by cholesterol. According to res...

Claims

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Application Information

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IPC IPC(8): G06F19/00
CPCG16C20/20G16C20/50
Inventor 芦秀丽赵琳琳史晓倩杨晓雄高兵魏杰
Owner LIAONING UNIVERSITY
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