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Daily Signal June 03, 2026 · 10 min read

Issue #122: Analysis of toxicity and mechanism of xylazine on testis with network toxicology and molecular docking strategy.

Protein Design Digest #122: Tocotrienol as a multi-target inhibitor of ICAM-1, VCAM-1, and E-selecti…

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Analysis of toxicity and mechanism of xylazine on testis with network toxicology and molecular docking strategy.

Xylazine, an alpha-2 adrenergic agonist originally developed as a veterinary sedative, has increasingly been detected as an adulterant in illicit drug supplies, particularly in combination with opioids such as fentanyl. This emerging pattern of misuse poses significant health risks and imposes a growing social burden, underscoring the urgent need to develop a rapid and comprehensive research strategy to investigate the potential toxicological mechanisms of xylazine. The present study aimed to comprehensively assess the toxicity of xylazine on the testis and its potential molecular mechanism using network toxicology and molecular docking analyses. By utilizing ChEMBL, STITCH, GeneCards, OMIM, TTD, and Drugbank databases, we predicted 126 xylazine-associated targets related to testis injury. Through further screening with STRING and Cytoscape software, 18 core targets in the testicular injury network, including steroid receptor coactivator (SRC) and Heat shock protein 90 alpha family class A member 1 (HSP90AA1), were obtained. GO and KEGG pathway analyses conducted through the DAVID database suggested that the core targets of xylazine-induced testicular toxicity may be enriched mainly in neuroactive ligand receptor interaction pathway, cancer pathways, apoptosis signaling pathways, and calcium signaling pathways. Molecular docking via AutoDock confirmed the strong binding between xylazine and the core targets. Together, these findings suggest that xylazine may be involved in regulating cell proliferation, cell apoptosis, and inflammation, which could potentially lead to testis injury. This study provides a theoretical basis for understanding the molecular mechanism of xylazine-induced testicular toxicity. In addition, network toxicology combined with molecular docking has provided new directions for the elucidation of the toxicity and mechanism of action of novel drugs.

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Also Worth Reading

Exploring the mechanism of saffron in treating viral myocarditis using network pharmacology and molecular docking.

Viral myocarditis (VM) is a cardiovascular disorder that can lead to heart failure and cardiogenic shock. Saffron, a traditional Chinese medicinal herb, has shown therapeutic potential against VM in numerous studies. However, the mechanisms through which saffron exerts its effects on VM remain poorly understood. Thus, this study aimed to elucidate the active compounds, molecular targets, and signaling pathways involved in saffron’s therapeutic action against VM by employing network pharmacology and molecular docking approaches. The active compounds and corresponding targets of saffron were retrieved from the Traditional Chinese Medicine Systems Pharmacology database. VM-associated targets were sourced from the GeneCards database. Overlapping targets between saffron and VM were then identified. Protein-protein interaction networks were established and analyzed utilizing the STRING platform and Cytoscape software to determine core targets. Furthermore, gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses were carried out utilizing Bioconductor in R to explore the potential biological activities and signaling pathways through which saffron may act against VM. Finally, molecular docking and model visualization were carried out using AutoDock Tools and PyMOL open-source software. From the database, we identified 4 active compounds in saffron with potential effects against VM: crocetin, isorhamnetin, kaempferol, and quercetin. A total of 60 corresponding targets were observed, with TNF, IL-6, IL-1β, CXCL8, and JUN emerging as core targets. Kyoto encyclopedia of genes and genomes enrichment analysis revealed 155 regulatory signaling pathways, among which the TNF, AGE-RAGE, and IL-17 signaling pathways, lipid metabolism, and atherosclerosis were the most prominent. Molecular docking results indicated that quercetin showed the strongest binding affinity toward IL-1β and CXCL8. The therapeutic effect of saffron against VM is not driven by a single factor, but rather involves multiple active compounds, targets, and signaling pathways.

Investigation of in vitro anticancer and antioxidant activities of various extracts of Bayramiç Beyazı nectarine, and molecular docking, molecular dynamics simulation, and protein-protein interaction network

Nectarine (Prunus persica var. nucipersica), due to its high phenolic content and antioxidant properties, holds significance for human health. The aim of this study was to evaluate the in vitro anticancer and antioxidant effects of the extracts obtained from the fruit and kernel of “Bayramiç Beyazı” nectarine, a geographically indicated fruit grown in Bayramiç district of Çanakkale. The anticancer effects of the methanol and aqueous ethanol extracts were evaluated on breast and colon cancer cell lines. Apoptotic fragmentation and mitochondrial membrane potential of fruit and kernel extracts were examined under fluorescence microscopy. Antioxidant activity and phenolic content were determined using DPPH, ABTS, and Folin-Ciocalteu (F-C) methods, respectively. Kernel extract has the highest antioxidant activity (DPPH IC₅₀= 0.15 ± 0.001 mg/mL). The fruit methanol, aqueous ethanol, and kernel aqueous ethanol extracts significantly reduced the fluorescent intensity of the cells. A combination study was conducted between the extracts and doxorubicin. Molecular docking and molecular dynamics (MD) simulation studies of some of the identified components were performed using the Glide/SP and Desmond against a drug target PRK1. The highest binding affinity with quercetin for targeting PRK1 was calculated as -8.789 kcal/mol. The average RMSD values were calculated between 3.43 ± 0.31 and 2.22 ± 0.30 Å throughout 500 ns MD simulations. A protein-protein interaction network analysis was performed for PRK1 using a systems biology approach to identify the highest scoring predicted proteins such as RHOA, MAP2K3, and MEFV. The investigation of the in vitro anticancer effects of “Bayramiç Beyazı” extracts and combined in silico analyses were carried out for the first time, and the outcomes of this study have promising potential for future studies.

Identification and Characterization of New Therapeutic Candidates for Naegleria fowleri- brain-eating Amoeba: A Multi-target Approach Based on 3D-QSAR, Molecular Docking, MM-GBSA, ADMET and Molecular Dynamics.

Background Naegleria fowleri is the most destructive and common brain-eating amoeba because it badly affects the human Central Nervous System (CNS), when amoeba in water goes up into the nose. N. fowleri also leads to PAM (primary amoebic meningoencephalitis) in humans. The lack of effective therapies for the treatment of PAM is a great drawback. The synthesis of new drug candidates for the treatment of this disease is time consuming and costly process. Aims & objectives Therefore, to reduce time and cost, already FDA-approved brain cancer drugs can be repurposed to get an effective drug for the management of Naegleria fowleri because compounds used to treat brain cancer also have antiviral activities. Methods For this purpose, an appropriate three-dimensional (3D-QSAR) model was created using the IC50 values of anti-brain cancer drugs. The QSAR (quantitative structure activity relationship) can provide suitable input for determining the structure of brain cancer drugs against Naegleria fowleri. The model validation was used as statistical parameters like r2 and q2. Results An appropriate 3D-QSAR was carried out with q2 and r2 calculated values like 0.9935 and 0.7249. The model QSAR also showed the predicted activities of various currently available and new drugs for brain cancer. The study was followed by molecular docking and MD simulation. Discussion The results of docking study revealed that the protein 6W7G shows a high binding affinity with Harmol, the most active compound. MD simulation of 6G6R protein showed an RMSD value of about 0.35 Å. Conclusion The present study indicated that the drug harmol could be an effective treatment for PAM in consideration of the 3D-QSAR, molecular docking, MD and ADME and toxicity analysis. However, further in vivo and in vitro studies are in process for the approval of this drug for the management of Naegleria fowleri.

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Analysis of toxicity and mechanism of xylazine on testis with network toxicology and molecular docking strategy.

Xylazine, an alpha-2 adrenergic agonist originally developed as a veterinary sedative, has increasingly been detected as an adulterant in illicit drug supplies, particularly in combination with opioids such as fentanyl. Read more →

Assessment of Antimicrobial Activity, Membrane Integrity, and Oxidative Stress of Green Synthesized Silver Nanoparticles: In Vitro and Molecular Docking Studies.

Silver nanoparticles were synthesized using Acacia karroo aqueous leaves extract for the first time, as evidenced by a characteristic UV-Vis absorption peak at 424 nm. Read more →

Integrated Molecular Docking and Gene Expression Analyses Suggest a Potential Interaction Between Diphtheria Toxin and Bcl-2 in HT-29 Colorectal Cancer Cells.

Diphtheria toxin (DT) has been reported to exhibit cytotoxic effects in several cancer models; however, the molecular mechanisms underlying its apoptotic activity remain incompletely understood. Read more →

Study on the Potential Mechanism of Bisphenol A-induced Human Diabetic Nephropathy Based on Network Toxicology and Molecular Docking.

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