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Method for distinguishing activities of complete agonist, partial agonist and antagonist of peroxisome proliferator-activated receptor gamma

A peroxidase and agonist technology, applied in the field of endocrine disruptor identification, can solve the problems of low sampling efficiency, discrimination of PPARγ interfering substances, inability to distinguish activities of complete agonists, partial agonists, and antagonists, and save the laboratory Cost and workload reduction effect

Active Publication Date: 2019-11-08
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Due to the limitations of the sampling efficiency of traditional molecular dynamics, the simulation of tens of ns or even hundreds of ns usually used in existing research is not enough to find a truly stable structure, which makes it difficult to use traditional molecular dynamics techniques alone Distinguishing the activity of PPARγ interfering substances
[0008] Molecular dynamic simulation (MD), traditional MD (cMD) technology is difficult to cross the high free energy barrier in a limited simulation time, so there is a problem of low sampling efficiency, and the research is only focused on a certain A class of substances with similar structures
Traditional MD techniques cannot distinguish the full agonist, partial agonist, and antagonist activities of PPARγ interfering substances

Method used

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  • Method for distinguishing activities of complete agonist, partial agonist and antagonist of peroxisome proliferator-activated receptor gamma
  • Method for distinguishing activities of complete agonist, partial agonist and antagonist of peroxisome proliferator-activated receptor gamma
  • Method for distinguishing activities of complete agonist, partial agonist and antagonist of peroxisome proliferator-activated receptor gamma

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Experimental program
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Embodiment 1

[0036] Research material and data collection of the present invention:

[0037] The substance used in this study is the substance that Mingliang Fang et al. analyzed from background indoor dust in 2015. The researcher analyzed a variety of substances from indoor dust in Beijing, including a variety of flame retardants and their metabolites. From PPARγ activation and binding experiments, it can be found that most of these substances have been confirmed as full agonists or partial agonists of PPARγ in previous studies. The researcher used rosiglitazone and the endogenous ligand 15d-PJG2 of PPAR as positive substances, and used the reporter gene method to study the PPARγ activity of these substances. Activity data for this study were derived from this study. Before using the data, the EC15 for each substance was first converted to equivalents relative to rosiglitazone and then logarithmic.

[0038] Receptor and Ligand Modeling:

[0039] The protein molecular structure templat...

Embodiment 2

[0051] Embodiment 1 experimental result:

[0052] The substance used in this study is the substance that Mingliang Fang et al. analyzed from background indoor dust in 2015. PPARγ activity data and affinity data for PPARγ binding ligands are derived from this researcher's article. The results are shown in Table 1.

[0053] Table 1 Substances and their activities in the literature NA: No definite data

[0054] compound EC15(μM) TPP 2.12 TPPi NA mono-ITP 3.6 Di-ITP 3.25 Tri-ITP 5.7 BYZGR 5.86 2,4,6-TIP 8.72 2,4,6-TBP 5.89 TCBPA 0.23 TBBPA 0.32 TBPP NA TBOEP NA TBBA 8.16 BDE47 5.2 3-OH-BDE47 2.01 6-OH-BDE47 NA TCS NA DiBP 4.47 DBP 6.73 BzB 2.94 TBMEHP 0.53 MEHP 1.26 15d-PJG2 0.51 rosiglitazone (positive control) 0.00132

[0055] H12 conformation and activity differentiation of PPARγ:

[0056] The free energy spectra...

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Abstract

The invention discloses a method for distinguishing the activities of a complete agonist, a partial agonist and an antagonist of a peroxisome proliferator-activated receptor gamma. The method comprises: modeling of the receptor and a ligand; molecular docking; simulation of conventional molecular dynamics; simulation of well-tempered meta-dynamic molecular dynamics; and construction of a pharmacophore. The method disclosed by the invention can quickly distinguish the activities of the PPARs gamma of different structural compounds, so that use of chemical drugs and cells in a conventional toxicity experiment process in a laboratory is greatly reduced, the workload in the laboratory is relieved, and expenses on the laboratory are saved; therefore, the activities of the PPARs gamma of the compounds are distinguished before QSAR (quantitative structure-activity relationship) modeling, and a QSAR model result is closer to an actual model; and a traditional QSAR is used more widely.

Description

technical field [0001] The invention belongs to the technical field of endocrine disruptor identification, and in particular relates to a method for distinguishing the activities of peroxidase-activated proliferation receptor gamma full agonists, partial agonists and antagonists. Background technique [0002] Endocrine disrupting chemicals (EDCs) only need a trace amount to produce significant adverse effects, so they have attracted people's attention. Endocrine disrupting effects mediated by nuclear receptors can be divided into two types: agonistic effects and antagonistic effects. Up to now, more than 142 million chemicals have been synthesized and registered by humans, and the number is still increasing. Among them, there are a large number of substances with potential endocrine disrupting effects that need to be identified. However, the existing in vivo and in vitro experimental techniques are also unable to cope with the ever-increasing number of compounds to be scree...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/53
CPCG01N33/53C07K14/70567G16C20/50G16B15/30C07K1/00G16C10/00G16B15/00G16B5/00G16C20/70C07K1/04
Inventor 刘红玲石来昊
Owner NANJING UNIV
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