Application of protein inhibitor t323 in antifertility

An anti-fertility, small molecule inhibitor technology, applied in the field of biomedicine, achieves good activity, novel structure, and improved screening accuracy

Active Publication Date: 2017-05-03
国家卫生健康委科学技术研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In 2012, scientists from Baylor College of Medicine in the United States, such as Matzuk, discovered a small molecule compound (+)-JQ1, which targets human BRDT and can effectively and reversibly prevent fertility. However, there are not many BRDT inhibitors at present. According to the research report, BRDT has great potential value as the target of male anti-fertility drugs due to its high tissue specificity, so finding effective BRDT protein inhibitors has positive significance for male anti-fertility drugs

Method used

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  • Application of protein inhibitor t323 in antifertility
  • Application of protein inhibitor t323 in antifertility
  • Application of protein inhibitor t323 in antifertility

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] The construction of embodiment 1 pharmacophore model

[0051] 1. Download the three-dimensional structure file of the co-crystal active conformation of human BRDT and JQ1 from the PDB database and input it into Discovery Studio 3.0 software, figure 1 The domain map of BRDT and the enantiomers of compound JQ1 are shown;

[0052] 2. Use the pharmacophore building block of Discovery Studio 3.0 to construct a pharmacophore model based on the interaction between BRDT and JQ1 complex, remove water molecules, add hydrogen bonds to form receptor structures;

[0053] 3. Set each parameter condition, set the parameters of the minimum structural feature and the maximum structural feature to 4 and 6 respectively, set the lipophilic site density parameter to 15, and set the polar site parameter to 20;

[0054] 4. Identify the active site according to the interaction mode between the acetyl-lysine binding pocket JQ1 and BRDT, cluster all the action sites, and obtain a pharmacophore ...

Embodiment 2

[0059] Example 2 drug class prediction

[0060] 1. Materials

[0061] The compound database of the National New Drug (Microbial) Screening Laboratory of the Institute of Pharmaceutical Biotechnology, Chinese Academy of Medical Sciences and the self-developed microbial natural product database MNPD.

[0062] 2. Lipinski's five-rule screening compound library

[0063] 80,000 compounds from the compound library were screened using Lipinski's rule of five to screen out compounds with toxic groups and active groups.

[0064] 3. Calculate the ADMET properties of the compound

[0065] Predict the properties of the compounds screened by Lipinski's five rules in terms of water solubility, human intestinal absorption, blood barrier permeability, cytochrome P4502D6 inhibition, liver toxicity, and plasma protein binding rate, and select a relative molecular mass below 500 , Calculate the compounds whose lipid-water partition coefficient CLgP is less than 5, the number of hydrogen bond ...

Embodiment 3

[0068] Embodiment 3 virtual screening based on pharmacophore model

[0069] The constructed pharmacophore model was input as a 3D query structure into the compound database (76984) filtered by Lipinski's five rules and predicted by ADMET for high-throughput virtual screening, and compounds matching more than half of the pharmacodynamic characteristic elements were retained. Finally, 270 qualified compounds were screened out.

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Abstract

The invention discloses application of a protein inhibitor T323 to fertility resistance. The T323 targets the bromine structural domain of a BRDT. The invention also discloses a platform for rational screening of male anti-fertility medicine. The inhibitor screened through the platform can be used for preparing the male anti-fertility medicine safely, effectively and reversibly.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to the application of protein inhibitor T323 in anti-fertility, more specifically, the application of a BRDT protein inhibitor T323 in anti-fertility. Background technique [0002] In recent years, with the development of reproductive medicine, the research and application of germ cells and early embryo development have been deepened, and many anti-fertility drugs have been discovered. Male contraceptives under research can be roughly divided into two categories: hormonal and non-hormonal. At present, research on hormonal contraceptives is more common. Steroidal contraceptives achieve the purpose of anti-fertility by inhibiting the secretion of human testosterone and thereby inhibiting the number of sperm produced, which can easily lead to endocrine disorders. It is likely to negatively affect androgen-dependent physiological functions, such as bone metabolism, muscle strength...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/47A61P15/16G01N33/68
CPCA61K31/47G01N33/68G01N2500/04
Inventor 王慧萍
Owner 国家卫生健康委科学技术研究所
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