Deciphering the Anti-psoriatic Mechanisms of TWH Compounds: An Integrated Approach of Network Pharmacology and Molecular Dynamics Simulation

Abstract

Background

Psoriasis, a prevalent immune-mediated inflammatory skin disease, has a complex pathogenesis involving genetic predisposition, immune system dysregulation, and environmental triggers. Despite its prevalence, treatment options remain limited. Tripteaser wilfordii Hook (TWH), a traditional Chinese medicine, has shown potential in treating psoriasis, and recent studies suggest that its therapeutic effects may be related to its ability to modulate the immune system and microecological balance, similar to how medical ozone therapy has been found to influence immune regulation and inflammation in psoriasis. This study aimed to explore the targets and pathways of psoriasis treatment, focusing on symptom relief, prevention of disease progression, improvement of quality of life, and the integration of psychological health. TWH compound preparation against psoriasis using network pharmacology and molecular dynamics.

Methods

The methodology involved screening active compounds of TWH from the TCMSP database and retrieving psoriasis-associated genes from multiple sources. Key hub genes were identified through topological analysis of the constructed protein–protein interaction (PPI) network with Cytoscape 3.8.2. Potential mechanisms were explored via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. The interaction between compounds and proteins was predicted using molecular docking and molecular dynamics simulations with Auto Dock Vina and Chimera 1.15.

Results

We identified 15 active compounds from TWH, along with 88 psoriasis-related targets. Network analysis identified key hubs, including AKT1, ESR1, TP53, STAT3, TNF, BCL2, JUN, HSP90AA1, CASP3, and RELA. Pathway enrichment analysis revealed mechanisms primarily involving inflammation and immune responses. SwissADME profiling nominated Zhebeiresinol, Kaempferol, and 5,8-Dihydroxy-7-(4-hydroxy-5- methylcoumarin-3-yl) coumarin as promising lead candidates. Molecular docking and dynamics simulations confirmed that 5,8-Dihydroxy-7-(4-hydroxy-5-methylcoumarin-3-yl) coumarin and kaempferol bind stably to the STAT3 protein. This binding is primarily driven by van der Waals forces, suggesting their potential as natural product-derived therapeutics for psoriasis.

Conclusions

We have identified fixed-dose combinations of 5,8-Dihydroxy-7-(4-hydroxy-5- methylcoumarin-3-yl) coumarin and kaempferol as part of novel target strategies for psoriasis, which inhibit specific JAK-STAT signaling pathway simultaneously, leading to superior efficacy and the ability to counter drug resistance.

Keywords

TWH compounds / Psoriasis / Network pharmacology / Molecular docking / Molecular dynamics simulations

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Funding

National Outstanding Youth Science Fund Project of National Natural Science Foundation of China(NSZD2023062)

the Postdoctoral Fellowship Program of CPSF(GZC20251765)

RIGHTS & PERMISSIONS

Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare