Integrating network toxicology， molecular docking， and molecular dynamics simulation to explore the mechanisms underlying depression induced by low‑chlorinated polychlorinated dibenzo‑p‑dioxins
10.11886/scjsws20260506002
- VernacularTitle:整合网络毒理学、分子对接与分子动力学模拟探究低氯代二苯并二噁英致抑郁症的机制
- Author:
Xueting YIN
1
;
Boyi CHU
1
;
Pengzhan YANG
1
;
Chengpeng ZHANG
1
Author Information
1. College of Traditional Chinese Medicine， Hubei University of Chinese Medicine， Wuhan 430065， China
- Publication Type:Journal Article
- Keywords:
Network toxicology;
Molecular docking;
Molecular dynamics simulation;
Depression;
Polychlorinated dibenzo‑p‑dioxins;
Low‑chlorinated polychlorinated dibenzo‑p‑dioxins
- From:
Sichuan Mental Health
2026;39(4):345-355
- CountryChina
- Language:Chinese
-
Abstract:
BackgroundPolychlorinated dibenzo‑p‑dioxins （PCDDs） is a type of global environmental pollutants， have been shown in numerous studies to exert neurotoxic effects. Nevertheless， existing research has predominantly focused on 2，3，7，8‑tetrachlorodibenzo‑p‑dioxin （2，3，7，8‑TCDD）. Whether low‑chlorinated PCDDs （LC‑PCDDs）， a subclass with fewer chlorine substitutions， can induce depression as well as the corresponding molecular mechanisms remains unclear. ObjectiveTo elucidate molecular mechanisms underlying depression induced by LC‑PCDDs， so as to provide evidence for environmental neuro-psychotoxicological risk assessment. Methods①Network toxicology. Four compounds， namely 2-monochlorodibenzo-p-dioxin （2-MCDD）， dichlorodibenzo-p-dioxin （DCDD）， 1，2，4‑trichlorodibenzo‑p‑dioxin （1，2，4-TrCDD）， and 2，3，7-TrCDD， were selected as research subjects. Their toxic profiles were predicted using public databases， and target genes associated with LC-PCDDs and depression were retrieved. The overlapping targets were imported into the STRING database to construct a protein-protein interaction （PPI） network. Topological analysis was subsequently performed via the CytoNCA plugin in Cytoscape to identify hub targets. Finally， Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analyses for these hub targets were completed in DAVID. ②Molecular docking. Docking simulations were conducted using AutoDock Tools 1.5.7， and the binding poses and interaction profiles of the resultant protein-ligand complexes were visualized using PyMOL （TM） 3.1.6.1. ③Molecular dynamics simulation. A 100-ns production simulation for the top-ranked docked complex was carried out using GROMACS 2025. The protein was parameterized with the AMBER99SB-ILDN force field， the ligand topologies were generated using GAFF2， and the two were then merged to construct the protein-ligand complex system. The complex was solvated in TIP3P water， and the system was adjusted to physiological ionic strength by adding 0.15 mol/L Na⁺/Cl⁻. Following energy minimization and sequential 2-ns equilibrations in canonical and isothermal-isobaric ensembles， a 100-ns production run was executed at 310 K and 1 bar. Results①Network toxicology analysis identified 10 hub targets （ESR1， HSP90AA1， PPARG， EGFR， MAPK1， MAPK14， AR， PGR， CDK2， and TGFBR1）， which were enriched in multiple critical signaling pathways. ②Molecular docking revealed that all four compounds exhibited strong binding affinities for hub targets， with 2-MCDD showing the highest binding affinity for PPARG （ΔG=-8.836 kcal/mol）. ③Molecular dynamics simulations demonstrated that the ligand-receptor complex formed by 2-MCDD and PPARG maintained a stable binding conformation throughout the 100-ns simulation. ConclusionLC-PCDDs may serve as significant environmental risk factors for depression， participating in its pathogenesis by mediating a multidimensional regulatory network involving metabolism， oxidative damage and apoptosis. ［Funded by Hubei Province Traditional Chinese Medicine Clinical Excellent Talents Project］.
