A Molecular-Dynamics-Guided Screening Pipeline Identifies Topical Glucocorticoid Receptor Modulators with Selective Epidermal Activation.

Abstract

Introduction: Topical corticosteroids remain the mainstay of psoriasis management but are limited by skin atrophy and barrier impairment. Developing safer, steroid-sparing therapy represents an unmet need in topical pharmacology. The glucocorticoid receptor (GR) plays a central role in epidermal homeostasis, yet selective activation by natural phytochemicals has not been systematically explored.

Methods: A molecular modeling framework integrating docking, molecular dynamics simulations, and pharmacophore conservation was established to evaluate GR engagement by four phytochemicals - sakuranetin, salvianolic acid B, lithospermic acid, and magnolol. Computational findings were compared with immunohistochemical analysis of total GR and phosphorylated Ser211-GR in psoriatic epidermal specimens derived from residual archived tissues.

Results: Salvianolic acid B and lithospermic acid displayed high docking affinity and stable retention of canonical GR contacts, whereas sakuranetin and magnolol exhibited moderate but consistent binding. Immunohistochemistry confirmed preserved GR abundance for all compounds, with lithospermic acid producing the greatest increase in Ser211 phosphorylation, consistent with differential receptor-associated signaling patterns. Computational and histological findings showed preliminary directional concordance between computational interaction profiles and tissue-level receptor-associated readouts.

Conclusion: This study demonstrates that integrating molecular modeling with receptor-associated histological analysis may assist in prioritizing natural compounds with potential GR-engagement properties. The proposed framework provides an exploratory and reproducible strategy for receptor-engagement prioritization in topical pharmacology and may support future investigation of bioactive phytochemicals in dermatologic research.