Estrogen interference activity quantitative prediction method based on nuclear receptor dimerization process

Abstract

The invention discloses an estrogen interference activity quantitative prediction method based on a nuclear receptor dimerization process, and belongs to the field of toxicology prediction. The preparation method comprises the following steps: obtaining a crystal structure of an estrogen receptor, determining an estrogen effect EC50 value of a ligand in the crystal structure, and then pre-treatingthe receptor protein of the crystal structure of the estrogen receptor and the ligand molecules; then constructing a complex to carry out molecular dynamics simulation on the complex, and calculatingthe free binding energy of the complex; establishing a quantitative correlation relationship, and fitting a regression prediction model; and finally carrying out estrogen interference activity prediction by utilizing the fitted regression model. According to the method, receptor and ligand binding, dimerization and co-factor recruitment processes are comprehensively considered, then the binding energy of the complex is calculated by utilizing a molecular dynamics method, and a prediction regression model is established, so that the prediction accuracy of the estrogen interference activity iseffectively improved.

Description

technical field [0001] The invention belongs to the field of predictive toxicology, in particular to a method for quantitatively predicting estrogen interference activity based on nuclear receptor dimerization process. Background technique [0002] Endocrine disrupting chemicals (EDCs) refer to substances that can interfere with the endocrine system of humans or animals and cause adverse health effects. EDCs are widely detected in the environment and in the human body. Exposure to endocrine disrupting substances not only causes a series of adverse health effects, but also causes huge economic losses. The cost of disease treatment caused by EDCs in the European Union is 217 billion US dollars, accounting for 1% of the total domestic production. 1.28% of the value of the United States, while the value of the United States reached 340 billion US dollars, accounting for 2.33% of GDP. Therefore, the identification and control of EDCs has always been a research hotspot in the fie...

AI Technical Summary

Problems solved by technology

[0005] In the existing research, there are mainly two aspects of research on the dimerization process, one is in vitro experiments (low-throughput, time-consuming and labor-intensive), and the other is simulation studies, but most of the current simulations are studies on monomers. Mainly because the step of recruiting co-factors is considered more important, the dimerization process is often neglected in the simulation process

Moreover, most of the existing simulation studies on dimers are based on an unfolded structure that is not the initial state of ER itself. The system is large, the process is complicated, and there are many factors to be considered; and this research based on dimers mainly It is to analyze the influence of this process on H12 (the ER receptor structure has 12 helices, and the 12th helix H12 is crucial for determining the mimetic effect of substances), it is difficult to predict the interference activity of estrogen

Therefore, the methods for predicting estrogen interference activity in the prior art are still based on nuclear receptors as monomers, using ligand receptor binding and co-factor recruitment processes to establish prediction models for mimicry or resistance effects, The dimerization process of EDCs after binding to the receptor is not fully considered, resulting in low accuracy when using existing methods to predict estrogen interference activity

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