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Hybrid pseudo-estrogen and anti-estrogen disruptor recognition method based on enhanced sampling molecular dynamics simulation

A molecular dynamics, anti-estrogen technology, applied in informatics, computational theoretical chemistry, instrumentation, etc., can solve problems such as limitations, and achieve the effect of low cost and high efficiency

Active Publication Date: 2019-12-24
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0032] The technical problem to be solved in the present invention is to provide a method for discovering the steady-state conformation of ERα based on the enhanced sampling molecular dynamics simulation method, so as to solve the limitations of existing methods in discovering the coexistence phenomenon of multi-stable conformations

Method used

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  • Hybrid pseudo-estrogen and anti-estrogen disruptor recognition method based on enhanced sampling molecular dynamics simulation
  • Hybrid pseudo-estrogen and anti-estrogen disruptor recognition method based on enhanced sampling molecular dynamics simulation
  • Hybrid pseudo-estrogen and anti-estrogen disruptor recognition method based on enhanced sampling molecular dynamics simulation

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Experimental program
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Effect test

Embodiment 1

[0066] Example 1: Molecular dynamics simulation of ERα

[0067] The human ERα structure was obtained from the ERα protein structure with PDB code 3erd obtained from the Protein Data Bank, and was checked for structural integrity and repaired by default residues under the Swiss-PdbViewer software. Ligand small molecules, including standard substances and endocrine disruptors bisphenols commonly found in the environment, are structurally optimized and docked with the receptor using the Surflex-Dock module in SYBYL 7.3 to form a ligand-receptor complex. The complex was simulated using the well-recognized enhanced sampling molecular dynamics simulation method—metadynamics simulation method—for enhanced sampling molecular dynamics simulation. The molecular simulation software used were gromacs and plumed software packages. Metadynamics simulations were carried out with the distances between L544 and E380 and between L544 and M522 in ERα as ensemble variables. Each metadynamics simu...

Embodiment 2

[0068] Example 2: Analysis of Molecular Dynamics Simulation Results

[0069]The molecular simulation trajectories obtained by the metadynamics simulation carried out in the present invention are used for further analysis. The dihedral angle formed by the α carbon atoms on the four amino acids M543, L539, A350 and L354 of ERα is used as set variable 1 (CV1, in radians), and the angle formed by the α carbon atoms on the three amino acids L539, M534 and M522 is CV2 (unit is radian), draw the characteristic map of free energy (Free Energy, unit is kJ / mol), describe the position of H12, obtain the lowest point of global and local free energy, and obtain the lowest point of free energy through conformational clustering. The representative conformation is the representative steady state conformation. According to the stable position of H12 in the representative steady-state conformation, the type of each steady-state conformation was judged. Finally, according to the type and quant...

Embodiment 3

[0070] Example 3: Analysis of the results of standard substances E2 and OHT

[0071] For the pure pseudo-standard material E2, the metadynamics simulation results show that the steady-state conformations of E2-ERα are all activated conformations ( Figure 2A ), which is consistent with the reported crystal structure of E2-ERα. The activated conformation of H12 forms a "steric hindrance" effect to selectively recruit CoA. Therefore, under the action of the pure mimetic compound E2, ERα forms an activated conformation, which leads to the selective recruitment of CoA by the receptor, which in turn leads to transcriptional activation and the generation of pure mimetic effects. For OHT of mixed pseudo- and resistant compounds, metadynamics simulation results show that OHT-ERα has multiple types of steady-state conformations ( Figure 2B ). OHT-ERα has three types of steady-state conformations: activation, blocking and competition, and the blocking and competition conformations a...

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Abstract

The invention discloses a hybrid pseudo-estrogen and anti-estrogen effect recognition and prediction method based on enhanced sampling molecular dynamics simulation. The method, based on nuclear receptor allosteric and co-regulator factor regulation and control mechanisms, and by adopting an enhanced sampling molecular dynamics simulation method, identifies local and global free energy lowest points and carries out dynamic trajectory clustering, extracts steady-state conformation of an estrogen receptor alpha under the action of a ligand compound, judges estrogen interference effect of a tested compound according to the relationship between the 12th spiral stable position of the receptor and a co-regulator factor recruitment / inhibition mechanism, and identifies and predicts pseudo effect and resistant effect and hybrid pseudo-estrogen and anti-estrogen disruptors. Compared with a traditional in-vitro experiment method, the method is lower in cost and higher in efficiency and prevents the problem of cell specificity of the hybrid pseudo-estrogen and anti-estrogen disruptors; and compared with an existing computer-aided screening method, the method can effectively identify steady-state conformation and realize prediction of hybrid pseudo-estrogen and anti-estrogen interference effects.

Description

technical field [0001] The invention belongs to the field of predictive toxicology using a computer program, in particular to a nuclear receptor-mediated mimetic, resistant and mixed mimetic and resistant endocrine disruptor screening based on enhanced sampling molecular dynamics simulation using computer software and method of prediction. Background technique [0002] Endocrine disrupting chemicals (EDCs) refer to compounds that cause harmful effects by disrupting the endocrine system. EDCs in ambient media 1,2 ,food 3 even human blood 4,5 It has been widely detected in China, and its exposure will cause a series of effects on human health and cause huge economic losses. The cost of diseases caused by EDCs in the European Union is 217 billion US dollars, accounting for 1.28% of the GDP, while that in the United States reaches 217 billion US dollars. $340 billion, or 2.33% of GDP 6,7 . Therefore, the identification and control of EDCs has always been a research hotspot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G16C10/00
CPCG16C10/00
Inventor 史薇陈钦畅于红霞
Owner NANJING UNIV
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