ABSTRACT
Background: Acne vulgaris is a common inflammatory skin condition caused by bacterial infections. Herbal remedies have gained attention for their potential in treating acne. This study investigated the antibacterial potential of Vitex negundo. Network pharmacology and molecular docking techniques were used to identify key targets and interactions relevant to acne therapy. Methods: Targets related to acne vulgaris were identified through open databases and literature reviews. Protein–protein interaction data were obtained from the Metascape and STRING databases, and network construction was performed using Cytoscape. Molecular docking was conducted using AutoDock to assess the binding affinity between Vitex negundo bioactives and bacterial targets associated with acne. Results: The network analysis revealed several key targets with high degrees of interaction. Molecular docking showed strong binding affinities between selected bioactives and bacterial targets, indicating their potential role in inhibiting acne-related bacterial growth. Conclusion: Vitex negundo bioactives demonstrate significant antibacterial potential, making them promising candidates for targeted acne therapy.
Key words: acne vulgaris, Vitex negundo, network pharmacology, molecular docking, bacterial targets, AutoDock, acne therapy, integrative analysis
INTRODUCTION
Herbal medicines are extensively used worldwide, with nearly 80% of the global population relying on traditional remedies. Despite their effectiveness, these systems often lack proper documentation. Integrating modern tools such as network pharmacology can bridge this gap, providing a scientific framework that can be used to validate and enhance traditional knowledge, paving the way for innovative and evidence-based therapeutic applications.[1,2]
Vitex negundo Linn., commonly known as “nirgundi” in Sanskrit, is a medicinal shrub belonging to the Verbenaceae family, with widespread distribution in tropical and temperate regions, particularly South Asia. Recognized in traditional medicine for its therapeutic potential, this plant is used to treat ailments such as asthma, jaundice, migraines, and wounds.[3] Its bioactive compounds, including polyphenols, terpenoids, and alkaloids, exhibit antioxidant, antimicrobial, anti-inflammatory, and anthelmintic properties. With its rich phytochemical profile, including p-hydroxybenzoic acid and β-sitosterol, Vitex negundo is a promising candidate for pharmaceutical applications, offering an affordable and accessible alternative in primary healthcare systems.[4–6]
Cutibacterium acnes is a key pathogen in acne, and its treatment typically involves oral antibiotics and topical formulations. However, the growing issue of antibiotic resistance poses significant challenges to conventional treatment strategies. Herbal medicines and their advanced formulations constitute viable alternatives, minimizing side effects while providing therapeutic efficacy.[7–9] Leveraging network pharmacology, a cutting-edge tool for elucidating drug mechanisms and multitarget interactions, this study explores the bioactive compounds of Vitex negundo and their molecular targets. Utilizing network pharmacology and molecular docking, the study seeks to predict and validate the therapeutic potential of Vitex negundo in combating acne.[10–13]
Acne vulgaris is a widespread dermatological condition for which few satisfactory treatments are available. Although conventional therapies such as benzoyl peroxide effectively suppress C. acnes, alternative approaches are increasingly being explored due to concerns about irritation and resistance. Among emerging diagnostic techniques, digital fluorescence photography (FP) has been identified as a fast, non-invasive tool for assessing acne and other skin conditions.[14,15] FP utilizes the autofluorescence properties of the skin, which can be excited by UV light and detected using specialized imaging systems. It is particularly useful in cosmetic and skin care research for evaluating pathological skin states such as acne and psoriasis. Recent advancements in FP technology, especially the integration of AI, have enhanced its potential for automated analysis and more precise diagnostics.[16,17] Additionally, new therapeutic approaches, such as Trachyspermum ammi (ajwain) essential oil, have shown promise in acne treatment, demonstrating significant reductions in lesion counts, sebum levels, and skin erythema. Given the rapid evolution of FP technology and AI-driven analysis, further research is needed to expand its applications in dermatology and skin care. This article explores the latest developments in acne diagnostics and treatment, emphasizing innovative imaging techniques and emerging natural therapies.[18–20]
Studies have explored the therapeutic potential of Vitex negundo in addressing various ailments, including asthma, jaundice, migraines, and wounds. Its bioactive compounds, such as polyphenols, terpenoids, and alkaloids, demonstrate potent antioxidant, antimicrobial, and anti-inflammatory properties. While network pharmacology and docking studies have been conducted on Vitex negundo, no literature exists on its bacterial network pharmacology.[21–23] This study investigates its bacterial network pharmacology and molecular interactions with acne-causing bacteria.
MATERIALS AND METHODS
Data mining and target identification
The bioactive compounds of Vitex negundo were mined from reliable phytochemical databases, including Dr. Duke's Phytochemical Database (https://phytochem.nal.usda.gov/phytochem/search) and the IMPPAT database (https://cb.imsc.res.in/imppat/), complemented by relevant literature reviews. The molecular targets of Vitex negundo phytochemicals were identified using the SwissTargetPrediction database (http://www.swisstargetprediction.ch/). Additionally, disease-specific targets for acne were retrieved from the GeneCards database (https://www.genecards.org/) and the Therapeutic Target Database (TTD; http://db.idrblab.net/ttd/). Common targets between the plant bioactives and acne-associated genes were identified using Venny 2.1 (https://bioinfogp.cnb.csic.es/tools/venny/).[24–26]
Network construction
A drug-disease-target interaction network was constructed using Cytoscape (v3.9.1, https://cytoscape.org/). Unique shapes and colors were employed to visually distinguish the drug, disease, and target node.[27,28]
Drug profile analysis
The drug-likeness properties of the phytochemicals were evaluated using Molsoft (https://molsoft.com/mprop/) based on Lipinski's rule of five. The ADMET profiles of the compounds were predicted using ADMETlab 3.0 (https://admetlab3.scbdd.com/server/screening).[29,30]
Gene ontology (GO) and pathway enrichment analysis
GO and pathway enrichment analyses for the identified targets were performed using Metascape (v3.5.20230501, https://metascape.org/gp/index.html#/main/step1) to determine the molecular mechanisms underlying the therapeutic effects of Vitex negundo.[31,32]
Protein–protein interaction (PPI) analysis
PPIs among the identified targets were analyzed using the STRING database (https://string-db.org/), providing insights into functional interactions and biological pathways.[33,34]
Molecular docking
The top five targets with the highest degree of connectivity from the constructed network were selected for molecular docking studies. Ligand structures of Vitex negundo bioactives were retrieved from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/), and protein target structures were obtained from the RCSB Protein Data Bank (https://www.rcsb.org/). Discovery Studio Visualizer 2021 was utilized for structure extraction and visualization, while PyRx (https://pyrx.sourceforge.io/) facilitated multiple ligand docking.[23,35,36]
RESULTS
Phytocompounds and target identification
A total of 230 phytocompounds of Vitex negundo were identified. Of these, several compounds were found to interact with the disease targets associated with acne-causing bacteria. A total of 123 targets with a probability value greater than 0.3 were identified using the SwissTargetPrediction database. Common potential targets between the plant and the bacteria were plotted using Venny 2.1. This analysis led to the identification of 28 key targets, which were further explored. The Venn plot of the common targets is presented in Figure 1. Table 1 comprising of the phytocompounds characters from the Vitex negundo.
Figure 1. Venn plot for the identification of potential targets.
Compound name | Molecular formula | Molecular weight (kDa) | NHBA | NHBD | MlogP | DLS |
Kaempferol | C15 H10 O6 | 286.05 | 6 | 4 | 1.61 | 0.50 |
Myricetin | C15 H10 O8 | 318.04 | 6 | 8 | 0.97 | -0.24 |
Quercetin | C15 H10 O7 | 302.04 | 7 | 5 | 1.19 | 0.52 |
Luteolin | C15 H10 O6 | 286.05 | 6 | 4 | 2.78 | 0.38 |
Palmitic acid | C16 H32 O2 | 256.24 | 2 | 1 | 6.64 | -0.54 |
Pentadecanoic acid | C15 H30 O2 | 242.22 | 2 | 1 | 6.13 | -0.54 |
Stearic acid | C18 H36 O2 | 284.27 | 2 | 1 | 7.65 | -0.54 |
Lauric acid | C12 H24 O2 | 200.18 | 2 | 1 | 4.62 | -0.54 |
Arachidic acid | C20 H40 O2 | 312.30 | 2 | 1 | 8.66 | -0.54 |
Myristic acid | C14 H28 O2 | 228.21 | 2 | 1 | 5.63 | -0.54 |
beta-D-Glucose | C6 H12 O6 | 180.06 | 6 | 5 | -3.02 | -0.12 |
Oleic acid | C18 H34 O2 | 282.26 | 2 | 1 | 7.11 | -0.30 |
Linoleic acid | C18 H32 O2 | 280.24 | 2 | 1 | 6.60 | -0.30 |
Linolenic acid | C18 H30 O2 | 278.22 | 2 | 1 | 5.88 | 0.09 |
Network construction
The connections between the bioactive compounds of Vitex negundo and target genes were determined using the SwissTargetPrediction database, leveraging chemical structure similarity to predict molecular targets. Acne-related genes were sourced from GeneCards and TTD, with common targets identified using Venny 2.1, forming the foundation for network construction in Cytoscape. The network, built for key Vitex negundo compounds-including kaempferol, myricetin, quercetin, peroxisome proliferator-activated receptor alpha (PPARA), apigenin, and luteolin-highlighted kaempferol as the most interconnected node (degree = 18), followed by myricetin (degree = 15), quercetin (degree = 14), PPARA (degree = 11), and apigenin and luteolin (degree = 10 each). These degree values suggest their potential significance in acne treatment. Figure 2 illustrates the network, using distinct colors and shapes to enhance clarity and interpretation.
Figure 2. Network of drug-targets-disease. TNKS, Tankyrase; PIM1, Proto-Oncogene, Serine/Threonine Kinase; PPARG, Peroxisome Proliferator-Activated Receptor Gamma; EGFR, Epidermal Growth Factor Receptor; ESR1, Estrogen Receptor 1; PTK2, Protein Tyrosine Kinase 2; F2, Coagulation Factor II (Thrombin); MMP13, Matrix Metallopeptidase 13; SRC, SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase; SYK, Spleen Tyrosine Kinase; MMP9, Matrix Metallopeptidase 9; ALOX5, Arachidonate 5-Lipoxygenase; XDH, Xanthine Dehydrogenase; MMP2, Matrix Metallopeptidase 2; CA3, Carbonic Anhydrase 3; CYP19A1, Cytochrome P450 Family 19 Subfamily A Member 1; PPARA, Peroxisome Proliferator-Activated Receptor Alpha; IGF1R, Insulin-like Growth Factor 1 Receptor; IL2, Interleukin 2; AHR, Aryl Hydrocarbon Receptor; TNF, Tumor Necrosis Factor; CNR2, Cannabinoid Receptor 2; TYR, Tyrosinase; CYP17A1, Cytochrome P450 Family 17 Subfamily A Member 1; NR1H3, Nuclear Receptor Subfamily 1 Group H Member 3; PTGS2, Prostaglandin-Endoperoxide Synthase 2; SHBG, Sex Hormone-Binding Globulin; MPO, Myeloperoxidase.
GO, pathway enrichment analysis, and protein interactions
In terms of biological processes (BP; Figure 3), the bubble plot highlights key processes with low false discovery rate (FDR) values, including inflammation regulation, lipid metabolism, and oxidative stress reduction, suggesting that Vitex negundo helps reduce cytokine release, balance hormonal signaling (e.g., estrogen pathways), and neutralize reactive oxygen species. In addition, regarding signaling pathways (Kyoto Encyclopedia of Genes and Genomes [KEGG]; Table 2, Figure 4), the heat map produced based on the pathway enrichment analysis shows that Vitex negundo combats Propionibacterium acnes infections by modulating inflammatory responses, regulating lipid metabolism, and mitigating oxidative stress, all of which are crucial for acne management. Finally, in terms of metabolic processes (Reactome; Figure 5), the PPI network highlights key targets such as TNF, MMPs, and ESR1, indicating that Vitex negundo may modulate inflammatory cytokines, regulate matrix degradation enzymes, and influence hormonal pathways to prevent acne-related inflammation and skin damage.
Figure 3. Heat map produced based on the path enrichment analysis. GO, gene ontology.
Figure 4. Biological process (gene ontology enrichment). FDR, false discovery rate.
Figure 5. Network of protein–protein interactions.
Pathway | Pathway description | Gene count | False discovery rate | Matching proteins |
hsa04915 | Estrogen signaling pathway | 5 | 0.0000125 | MMP2, EGFR, MMP9, SRC, ESR1 |
hsa04370 | VEGF signaling pathway | 3 | 0.0008700 | PTK2, PTGS2, SRC |
hsa04510 | Focal adhesion | 4 | 0.0012000 | EGFR, PTK2, SRC, IGF1R |
hsa05163 | Human cytomegalovirus infection | 4 | 0.0014000 | EGFR, PTK2, PTGS2, SRC |
hsa04657 | IL-17 signaling pathway | 3 | 0.0020000 | MMP13, PTGS2, MMP9 |
hsa04625 | C-type lectin receptor signaling pathway | 3 | 0.0024000 | PTGS2, SRC, SYK |
hsa04670 | Leukocyte transendothelial migration | 3 | 0.0030000 | MMP2, PTK2, MMP9 |
hsa04151 | PI3K-Akt signaling pathway | 4 | 0.0055000 | EGFR, PTK2, SYK, IGF1R |
hsa04921 | Oxytocin signaling pathway | 3 | 0.0059000 | EGFR, PTGS2, SRC |
hsa05167 | Kaposi sarcoma-associated herpesvirus infection | 3 | 0.0107000 | PTGS2, SRC, SYK |
hsa04015 | Rap1 signaling pathway | 3 | 0.0127000 | EGFR, SRC, IGF1R |
hsa00590 | Arachidonic acid metabolism | 2 | 0.0193000 | PTGS2, ALOX5 |
hsa04144 | Endocytosis | 3 | 0.0193000 | EGFR, SRC, IGF1R |
hsa04664 | Fc epsilon RI signaling pathway | 2 | 0.0211000 | ALOX5, SYK |
hsa04917 | Prolactin signaling pathway | 2 | 0.0211000 | SRC, ESR1 |
hsa05120 | Epithelial cell signaling in Helicobacter pylori infection | 2 | 0.0211000 | EGFR, SRC |
hsa05100 | Bacterial invasion of epithelial cells | 2 | 0.0217000 | PTK2, SRC |
hsa04064 | NF-κB signaling pathway | 2 | 0.0353000 | PTGS2, SYK |
hsa04066 | HIF-1 signaling pathway | 2 | 0.0353000 | EGFR, IGF1R |
hsa04668 | TNF signaling pathway | 2 | 0.0388000 | PTGS2, MMP9 |
hsa05135 | Yersinia infection | 2 | 0.0461000 | PTK2, SRC |
hsa04068 | FoxO signaling pathway | 2 | 0.0466000 | EGFR, IGF1R |
Molecular docking
The highest binding affinity was associated with kaempferol, myricetin, quercetin, and luteolin. These ligands, along with PPARA and apigenin, were further docked using PyRx software based on their associations found in the constructed network. The best five conformations were shown by TNKS_Luteoline (Figure 6), MPO_Myrectin, MMP13_Myrectin, MMP13_ Kaempferol, and MPO_Quercetin, with binding energies of -10.1, -9.5, -9.5, -9.4, and -9.2 kcal/mol, respectively.
Figure 6. Molecular docking interactions of TNKS with luteolin. (A) 3D binding pose of luteolin in the TNKS active site, showing key hydrogen bonds and hydrophobic interactions. (B) 2D interaction map highlighting bonding interactions between luteolin and TNKS residues, including hydrogen bonds and π-π stacking.
DISCUSSION
Approximately 80% of the world's population depends on herbal remedies for disease prevention and treatment. In this study, Vitex negundo was analyzed for its potential use against acne vulgaris using a network pharmacology approach. A total of 230 phytocompounds were identified, of which 28 showed interactions with acne-related bacterial targets.[37,38] The network analysis identified kaempferol, myricetin, and quercetin as key compounds, with kaempferol having the highest edge count. These compounds likely modulate inflammatory responses, lipid metabolism, and oxidative stress pathways, as highlighted in enrichment analyses.[39] PPI analysis further identified targets such as TNF, MMPs, and ESR1, emphasizing the potential of Vitex negundo in regulating cytokine release, enzyme activity, and hormonal balance. The docking results revealed that TNKS_Luteolin exhibited the highest binding affinity (-10.1 kcal/mol), followed by MPO_Myrectin, MMP13_Myrectin, MMP13_Kaempferol, and MPO_Quercetin.[40] The strong binding energies indicate a favorable interaction between these ligands and their respective targets, suggesting their potential as promising candidates for further investigation in drug development. The significant binding affinity of luteolin and myricetin highlights their role in stabilizing protein-ligand complexes, supporting their therapeutic relevance.[41,42]
CONCLUSION
This study identified 230 phytocompounds from Vitex negundo and explored their interactions with acne-related targets. A total of 123 targets were identified, with 28 common targets between the plant and P. acnes. Network analysis highlighted key compounds such as kaempferol, myricetin, and quercetin. GO and pathway enrichment revealed that Vitex negundo modulates inflammation, lipid metabolism, and oxidative stress, targeting key proteins such as TNF, MMPs, and ESR1. The docking results showed that TNKS_Luteolin exhibited the highest binding affinity of -10.1 kcal/mol, indicating its strong interaction with the target protein. These findings suggest that Vitex negundo has potential as a natural anti-acne therapy, and further investigations are needed for formulation development.
DECLARATIONS
Acknowledgement
We would like to thank the KLE Academy of Higher Education and Research, Karnataka, India and the MET Institute of Pharmacy, BKC, affiliated with Savitribai Phule Pune University, Nashik, India, for their constant support and for providing all the facilities required to conduct this research.
Author contributions
Balekundri A: Writing and revision of the first draft. Ahire ED: English editing and proofreading. Both authors agreed on the final version and submitted the article.
Source of funding
No funding was received.
Ethical approval
Not applicable.
Informed consent
Not applicable.
Conflict of interest
Eknath D. Ahire is an editorial board member of the journal. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and his research group.
Use of large language models, AI and machine learning tools
None declared.
Data availability statement
Supplementary data will be made available upon request.
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