A method for identification of mixed pseudo- and anti-estrogen disruptors based on enhanced sampling molecular dynamics simulation

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

Active Publication Date: 2021-12-24
NANJING UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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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

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  • A method for identification of mixed pseudo- and anti-estrogen disruptors based on enhanced sampling molecular dynamics simulation
  • A method for identification of mixed pseudo- and anti-estrogen disruptors based on enhanced sampling molecular dynamics simulation
  • A method for identification of mixed pseudo- and anti-estrogen disruptors based on enhanced sampling molecular dynamics simulation

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Experimental program
Comparison scheme
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 database, and the integrity of the structure was checked and the default residues were repaired by the Swiss-PdbViewer software. Ligand small molecules, including standard substances and endocrine disruptor bisphenols commonly found in the environment, are structurally optimized and docked in the receptor using the Surflex-Dock module in SYBYL 7.3 to form a ligand-receptor complex. The complex is subjected to enhanced sampling molecular dynamics simulation using the widely recognized enhanced sampling molecular dynamics simulation method—metadynamics simulation method—and the molecular simulation software used is gromacs and plumed software packages. The distance between L544 and E380 and between L544 and M522 in ERα is used as the set variable to carry out metadynamics simulation. The time of each meta...

Embodiment 2

[0068] Embodiment 2: analysis of molecular dynamics simulation results

[0069]The molecular simulation trajectory obtained from the metadynamics simulation carried out in the present invention is 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 the set variable 1 (CV1, in radians), and the angle formed by the α-carbon atoms on the three amino acids L539, M534, and M522 For CV2 (unit is radian), draw the free energy (Free Energy, unit is kJ / mol) feature map, describe the position of H12, get 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 H12 stable position of the representative steady-state conformation, the type of each steady-state conformation was judged. Finally, according to the type and quantity of t...

Embodiment 3

[0070] Embodiment 3: the result analysis of standard substance E2, OHT

[0071] For E2 of the pure pseudo-standard substance, the metadynamics simulation results show that the steady-state conformation of E2-ERα is the active conformation ( 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 pure mimetic compound E2, ERα forms an activated conformation, leading to the selective recruitment of CoA by the receptor, which in turn leads to transcriptional activation and pure mimetic effects. For the OHT of mixed pseudo-resistant compounds, the metadynamics simulation results show that OHT-ERα has various types of steady-state conformations ( Figure 2B ). OHT-ERα has three types of steady-state conformations: active, blocking and competing, and the blocking and competing conformations are consistent with the reported crystal...

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Abstract

The invention discloses a method for identifying and predicting mixed quasi-anti-estrogen effects based on enhanced sampling molecular dynamics simulation. Based on the regulation mechanism of nuclear receptor allosteric and co-regulatory factors, the enhanced sampling molecular dynamics simulation method is adopted. Identify local and global free energy minimums and perform dynamic trajectory clustering to extract the steady-state conformation of estrogen receptor α under the action of ligand compounds, and based on the relationship between the stable position of the receptor's No. 12 helix and the recruitment / inhibition mechanism of co-regulators , to judge the estrogen interference effect of the tested compound, to identify and predict mimics, resistance and mixed mimics and resistance interferers. Compared with the traditional in vitro experimental method, this method has low cost and higher efficiency, and avoids the cell-specific problem of mixed pseudo- and resistant interfering substances; compared with the existing computer-aided screening method, this method can effectively identify stable state conformation, to realize the prediction of mixed pseudo- and anti-estrogen interference effects.

Description

technical field [0001] The invention belongs to the field of predictive toxicology using computer programs, in particular to a nuclear receptor-mediated screening of mimicry, resistance and mixed mimicry and resistance endocrine disruptors based on enhanced sampling molecular dynamics simulation using computer software. method of prediction. Background technique [0002] Endocrine disrupting chemicals (EDCs) refer to compounds that cause harmful effects by interfering with the endocrine system. EDCs in ambient media 1,2 ,food 3 even human blood 4,5 It has been widely detected in EDCs, and its exposure will cause a series of impacts 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 GDP, while that of the United States reaches $340 billion, or 2.33% of GDP 6,7 . Therefore, the identification and control of EDCs has been a research hotspot in the field of environment...

Claims

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Application Information

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