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Thyroid hormone disruptor virtual screening and interference activity quantitative calculating method based on nuclear receptor coregulator

一种甲状腺激素、共调节因子的技术，应用在预测毒理学领域，能够解决筛选和预测不准确等问题，达到定性和定量预测结果可靠、效率高、操作简单的效果

Active Publication Date: 2016-08-24
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is to provide a virtual screening method for thyroid hormone disruptors based on nuclear receptor co-regulators to solve the problems of inaccurate screening and prediction in the prior art

Method used

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  • Thyroid hormone disruptor virtual screening and interference activity quantitative calculating method based on nuclear receptor coregulator
  • Thyroid hormone disruptor virtual screening and interference activity quantitative calculating method based on nuclear receptor coregulator
  • Thyroid hormone disruptor virtual screening and interference activity quantitative calculating method based on nuclear receptor coregulator

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Embodiment 1

[0052] The initial structure of human TRα and TRβ was constructed by using the method of homology modeling, and the main parts were respectively based on the human TRα and TRβ (PDB numbers 4LNX and 1NQ0) obtained through experiments in the existing literature as templates, and the softness between H11 and H12 The chain uses the receptor with PDB number 1A52 as a template, and the resulting structure is tested by Lagren diagram. Select 8 OH-PBDE molecules and triiodothyronine (T3) as ligands, use the Surflex-Dock module in SYBYL 7.3 to dock the ligands in the receptor to form a ligand-receptor complex, and calculate Docking scoring value. The complex was subjected to 20ns MD simulation with the gromacs package. The MD simulation process is as follows: after the ligand and receptor are endowed with the CHARMM force field, the complex is immersed in TIP3P model water, and sodium ions or chloride ions are added to balance the charge of the system. After energy convergence and tem...

Embodiment 2

[0056] The initial structure of rat TRα and TRβ was constructed by homology modeling method. Since the only TR receptors obtained by scholars through experiments are human TR, the main parts are human TRα and TRβ (PDB codes are 4LNX and 1NQ0 respectively). ) as a template, and the flexible chain between H11 and H12 used the receptor with PDB number 1A52 as a template, and the resulting structure passed the Lagren diagram test. Select 16 OH-PBDE molecules and T3 as ligands, dock the ligands in the receptor to form a ligand-receptor complex, and use the gromacs software package for MD simulation of at least 20 ns. The MD simulation process is as follows: after the ligand and receptor are endowed with the CHARMM force field, the complex is immersed in TIP3P model water, and sodium ions or chloride ions are added to balance the charge of the system. After energy convergence and temperature rise, the system is maintained at 300K and 1 Atmospheric pressure; Molecular dynamics simula...

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Abstract

The invention discloses a thyroid hormone disruptor virtual screening and interference activity quantitative calculating method based on a nuclear receptor coregulator. The method is based on a nuclear receptor coregulator regulation mechanism, molecular dynamics simulation is adopted in combination with a free energy calculation method, the thyroid hormone interference effect of a tested compound is judged through the stable position of 12 spiral, back kick of thyroid hormones and the mutual relation between a co-activator and a co-repressor, positive resistance, negative resistance and the fitting effect are differentiated, and magnitude of related activity is predicted by calculating ligand-receptor binding free energy. Compared with the prior art, the method is low in cost, simple in operation and higher in efficiency compared with a traditional in-vitro screening method; compared with other virtual screening methods, by means of the method, the molecular action mechanism is taken into consideration more completely, fitting and resistance can be differentiated, and a qualitative and quantitative predication result is more reliable.

Description

technical field [0001] The invention belongs to the field of predictive toxicology, and in particular relates to a virtual screening of thyroid hormone interferents based on nuclear receptor co-regulators and a quantitative calculation method for their interference activities. Background technique [0002] Thyroid hormones are important hormones in organisms, which play an important role in the growth, differentiation, metabolism and energy balance of organisms. Thyroid hormone interfering substances can affect the development of the fetal brain and central nervous system, affect the development of the heart, and cause various diseases. The harm cannot be ignored. As more and more synthetic or naturally occurring chemicals have been detected to have thyroid disrupting activity, such as polybrominated diphenyl ethers, polychlorinated biphenyls, bisphenol A, etc., these chemicals have received widespread attention. In order to screen suspected thyroid hormone-interfering subs...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G06F19/00G16B5/00G16B15/30G16B20/00G16B20/30
CPCG16Z99/00G16B5/00G16B20/30G16B20/00G16B15/30G01N2333/723G16B15/00
Inventor 于红霞史薇陈钦畅王小享
Owner NANJING UNIV
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