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Purpose <p>Stress-related disorders are increasingly prevalent worldwide and are strongly associated with dysregulation of glucocorticoids (GCs) and their receptor, the glucocorticoid receptor (NR3C1). Although conventional pharmacological treatments are available, they often cause adverse effects, necessitating safer alternatives.</p> Methods <p>A structure based virtual screening (SBVS) strategy was employed to screen phytochemicals derived from medicinal plants using multi-tier docking (HTVS, SP, and XP modes) implemented in the Schrödinger suite. Binding affinities were validated through MMGBSA calculations. The dynamic stability of protein-ligand complexes was investigated through all-atom molecular dynamics (MD) simulation, followed by principal component analysis (PCA) based free energy landscape (FEL) analysis, MM-PBSA binding free energy calculations, per-residue decomposition, and DSSP-based secondary structural assessment.</p> Results <p>SBVS strategy identified three phytochemicals (Miroestrol, Neridienone A, and IMPHY002216) with favourable GLIDE docking scores (–12.35 kcal/mol to − 12.85 kcal/mol) and MM/GBSA energies (–48.41 kcal/mol to − 55.59 kcal/mol) against NR3C1. Key residues such as Met560, Asn564, Gln570, Arg611, and Gln642 aided stabilize the NR3C1-phytochemical complexes through hydrogen bond interactions. Pharmacokinetic analysis revealed good oral bioavailability for therapeutic application. Additionally, molecular MDS, followed by essential dynamics (ED) analysis incorporating PCA-based FEL analysis, substantiated the structural stability of phytochemicals-NR3C1 complexes. Furthermore, MM-PBSA post-dynamics analysis revealed significant binding affinities.</p> Conclusion <p>This comprehensive in silico investigation identified Miroestrol, Neridienone A, and IMPHY002216 as promising phytochemical modulators of the NR3C1 receptor. Among them, Neridienone A demonstrated favourable dynamic stability and binding affinity, highlighting its potential as a novel lead compound for stress management.</p> Graphical Abstract <p></p>

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Structure-Guided Discovery of Phytochemical Leads Targeting the Glucocorticoid Receptor (NR3C1) for Anti-Stress Activity: Computational Insights from Multi-Tier Virtual Screening and Structural Dynamics

  • 期刊论文

  • 发表日期：

    2026年3月4日

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  • Shanthini Karuppiah,
  • Manikandan Jayaraman,
  • Maharaja Muthuvairam Subbulakshmi,
  • Jeyakanthan Jeyaraman,
  • Komalavalli Narayanaswamy

摘要

Purpose

Stress-related disorders are increasingly prevalent worldwide and are strongly associated with dysregulation of glucocorticoids (GCs) and their receptor, the glucocorticoid receptor (NR3C1). Although conventional pharmacological treatments are available, they often cause adverse effects, necessitating safer alternatives.

Methods

A structure based virtual screening (SBVS) strategy was employed to screen phytochemicals derived from medicinal plants using multi-tier docking (HTVS, SP, and XP modes) implemented in the Schrödinger suite. Binding affinities were validated through MMGBSA calculations. The dynamic stability of protein-ligand complexes was investigated through all-atom molecular dynamics (MD) simulation, followed by principal component analysis (PCA) based free energy landscape (FEL) analysis, MM-PBSA binding free energy calculations, per-residue decomposition, and DSSP-based secondary structural assessment.

Results

SBVS strategy identified three phytochemicals (Miroestrol, Neridienone A, and IMPHY002216) with favourable GLIDE docking scores (–12.35 kcal/mol to − 12.85 kcal/mol) and MM/GBSA energies (–48.41 kcal/mol to − 55.59 kcal/mol) against NR3C1. Key residues such as Met560, Asn564, Gln570, Arg611, and Gln642 aided stabilize the NR3C1-phytochemical complexes through hydrogen bond interactions. Pharmacokinetic analysis revealed good oral bioavailability for therapeutic application. Additionally, molecular MDS, followed by essential dynamics (ED) analysis incorporating PCA-based FEL analysis, substantiated the structural stability of phytochemicals-NR3C1 complexes. Furthermore, MM-PBSA post-dynamics analysis revealed significant binding affinities.

Conclusion

This comprehensive in silico investigation identified Miroestrol, Neridienone A, and IMPHY002216 as promising phytochemical modulators of the NR3C1 receptor. Among them, Neridienone A demonstrated favourable dynamic stability and binding affinity, highlighting its potential as a novel lead compound for stress management.

Graphical Abstract