J Genet Eng Biotechnol. 2025 Jun;23(2):100485. doi: 10.1016/j.jgeb.2025.100485. Epub 2025 Mar 29.

ABSTRACT

INTRODUCTION: Warts are dermal disorders resulting from HPV infection and can be transmitted by direct contact. Existing treatment approaches, such as topical treatment with salicylate, have low efficiency and demonstrate side effects. Thus, the discovery of potent drug treatments for skin warts is necessary. Here we propose the use of alternative medications for the possible treatment of skin warts with the help of comparative transcriptome analysis and drug repurposing approaches.

METHODS: Gene expression datasets related to HPV-induced warts and cervical cancer were extracted from the GEO database. Differentially expressed genes (DEGs) were identified using DESeq2 in the Galaxy database. Upregulated DEGs were assessed for druggability using the DGIdb tool. Gene ontology and enrichment analysis were performed to investigate the characteristics of druggable DEGs. A molecular docking virtual screening was conducted using PyRx software to identify potential therapeutic targets for skin warts. The interactions between selected drug candidates and the target protein were analyzed using the BIOVIA Discovery Studio. The physicochemical characteristics of potential pharmaceuticals were evaluated using the SwissADME database. Finally, the molecular dynamics (MD) simulation was performed to validate the stability and dynamic behavior of drug-protein interactions.

RESULTS: Based on the findings from gene expression profiling, Integrin Alpha-X (ITGAX, CD11c) has been identified as a candidate protein that is significantly upregulated in individuals afflicted with skin warts. Integrin Alpha-X plays a crucial role in mediating intercellular interactions during inflammatory processes and notably enhances the adhesion and chemotactic activity of monocytes. Through molecular docking, MD, and physicochemical analyses, it has been demonstrated that dihydroergotamine effectively inhibits the ITGAX protein, suggesting its potential as a therapeutic agent for the management of skin warts.

CONCLUSION: Dihydroergotamine can be repurposed as a potential drug in the treatment of skin warts by targeting Integrin Alpha-X protein.

PMID:40390498 | DOI:10.1016/j.jgeb.2025.100485

J Genet Eng Biotechnol. 2025 Jun;23(2):100502. doi: 10.1016/j.jgeb.2025.100502. Epub 2025 May 12.

ABSTRACT

Insomnia is a prevalent sleep disorder characterized by difficulty initiating or maintaining sleep, leading to severe health complications, increased mortality, and substantial socioeconomic burdens. Despite therapeutic advancements, effective pharmacological interventions remain limited, necessitating alternative approaches for drug discovery. This study aimed to identify potential therapeutic targets for insomnia by integrating gene network analysis, genomic data, and bioinformatics-driven drug repurposing strategies, aligning with the United Nations' Sustainable Development Goal (SDG) 3: Good Health and Well-being. Insomnia-associated Single Nucleotide Polymorphisms (SNPs) were retrieved from the GWAS catalog, yielding 3,952 loci. Insomnia risk genes were identified by linking these loci to proximal SNPs (r2 ≥ 0.8) in Asian populations using HaploReg v4.2, resulting in 1,765 candidate genes. A bioinformatics pipeline incorporating ten functional annotations and drug-gene interaction was employed to prioritize gene targets and identify novel repurposed drugs with potential biological relevance to insomnia. Drug-Gene Interaction Database (DGIdb) analysis identified seven druggable targets among 27 biologically significant insomnia risk genes, corresponding to 12 existing drugs. Notably, NRXN1 emerged as a highly promising target due to its strong functional annotation score and its known interaction with Duloxetine hydrochloride and nicotine polacrilex. This study underscores the potential of bioinformatics-driven gene network analysis in identifying drug repurposing candidates for insomnia. Further experimental validation is warranted to elucidate the therapeutic mechanisms of NRXN1 modulation in insomnia treatment.

PMID:40390493 | DOI:10.1016/j.jgeb.2025.100502

J Biomed Inform. 2025 May 17:104843. doi: 10.1016/j.jbi.2025.104843. Online ahead of print.

ABSTRACT

Drug repositioning, pivotal in current pharmaceutical development, aims to find new uses for existing drugs, offering an efficient and cost-effective path to drug discovery. In recent years, graph neural network-based deep learning methods have achieved significant success in drug repositioning tasks. However, few studies have analyzed the characteristics of datasets to mitigate potential data biases. In this paper, we analyzed three commonly used drug repositioning datasets and identified a consistent characteristic among them: a trend of node polarization, characterized by the presence of popular entities (those commonly occurring and extensively associated) and long-tail entities (those appearing less frequently with fewer associations). Based on this finding, we propose a deep learning framework with a debiasing mechanism, called DRDM. The framework excels in addressing popular entities' biases, which often overshadow the subtle patterns in long-tail entities-key for novel insights. DRDM dynamically adjusts association weights during training, enhancing long-tail entity representation and reducing bias. In addition, we employ dual-view contrastive learning to provide rich supervisory signals, thereby further enhancing the model's robustness. We conducted experiments with our method on these three datasets, and the results demonstrated that our approach exhibits strong competitiveness compared to competing models. Case studies further highlighted the potential of the model in practical applications, which could provide new insights for future drug discovery.

PMID:40389101 | DOI:10.1016/j.jbi.2025.104843

Medicine (Baltimore). 2025 May 16;104(20):e42411. doi: 10.1097/MD.0000000000042411.

ABSTRACT

Currently, there remains a significant gap in effective pharmacologic interventions for neonatal respiratory distress syndrome (NRDS). To address this critical unmet medical need, we aimed to systematically identify novel therapeutic targets and preventive strategies through comprehensive integration and analysis of multiple publicly accessible datasets. In this study, we employed an integrative approach combining druggable genome data, cis-expression quantitative trait loci (cis-eQTL) from human blood and lung tissues, and genome-wide association study summary statistics for neonatal respiratory distress. We performed two-sample Mendelian randomization (TSMR) analysis to investigate potential causal relationships between druggable genes and neonatal respiratory distress. To strengthen causal inference, we performed Bayesian co-localization analyses. Furthermore, we conducted phenome-wide Mendelian randomization (Phe-MR) to systematically evaluate potential side effects and alternative therapeutic indications associated with the identified candidate drug targets. Finally, we interrogated existing drug databases to identify actionable pharmacological agents targeting the identified genes. All 3 genes (LTBR, NAAA, CSNK1G2) were analyzed by Bayesian co-localization (PH4 > 75%). CSNK1G2 (lung eQTL, odds ratio [OR]: 0.419, 95% CI: 0.185-0.948, P = .037; blood eQTL, OR: 4.255, 95% CI: 1.346-13.455, P = .014; Gtex whole blood eQTL, OR: 4.966, 95% CI: 1.104-22.332, P = .037). LTBR (lung eQTL, OR: 0.550, 95% CI: 0.354-0.856, P = .008; blood eQTL, OR: 0.347, 95% CI: 0.179-0.671, P = .002; Gtex whole blood eQTL, OR: 0.059, 95% CI: 0.0.007-0.478, P = .008). NAAA (lung eQTL, OR: 0.717, 95% CI: 0.555-0.925, P = .011; Gtex whole blood eQTL, OR: 0.660, 95% CI: 0.476-0.913, P = .012). Drug repurposing analyses support the possibility that etanercept and asciminib hydrochloride may treat neonatal respiratory distress by activating LTBR. This study demonstrated that LTBR, NAAA, and CSNK1G2 may serve as promising biomarkers and therapeutic targets for NRDS.

PMID:40388790 | DOI:10.1097/MD.0000000000042411

Circulation. 2025 May 20;151(20):1449-1450. doi: 10.1161/CIRCULATIONAHA.125.074556. Epub 2025 May 19.

NO ABSTRACT

PMID:40388510 | DOI:10.1161/CIRCULATIONAHA.125.074556

J Vis Exp. 2025 May 2;(219). doi: 10.3791/67831.

ABSTRACT

RASopathies are genetic syndromes caused by ERK hyperactivation and resulting in multisystemic diseases that can also lead to cancer predisposition. Despite a broad genetic heterogeneity, germline gain-of-function mutations in key regulators of the RAS-MAPK pathway underlie the majority of the cases, and, thanks to advanced sequencing techniques, potentially pathogenic variants affecting the RAS-MAPK pathway continue to be identified. Functional validation of the pathogenicity of these variants, essential for accurate diagnosis, requires fast and reliable protocols, preferably in vivo. Given the scarcity of effective treatments in early childhood, such protocols, especially if scalable in cost-effective animal models, can be instrumental in offering a preclinical ground for drug repositioning/repurposing. Here we describe step-by-step the protocol for rapid generation of transient RASopathy models in zebrafish embryos and direct inspection of live disease-associated ERK activity changes occurring already during gastrulation through real-time multispectral Förster resonance energy transfer (FRET) imaging. The protocol uses a transgenic ERK reporter recently established and integrated with the hardware of commercial microscopes. We provide an example application for Noonan syndrome (NS) zebrafish models obtained by expression of the Shp2D61G. We describe a straightforward method that enables registration of ERK signal change in the NS fish model before and after pharmacological signal modulation by available low-dose MEK inhibitors. We detail how to generate, retrieve, and assess ratiometric FRET signals from multispectral acquisitions before and after treatment and how to cross-validate the results via classical immunofluorescence on whole embryos at early stages. We then describe how, via examining standard morphometric parameters, to query late changes in embryo shape, indicative of a resulting impairment of gastrulation, in the same embryos whose ERK activity is assessed by live FRET at 6 h post fertilization.

PMID:40388378 | DOI:10.3791/67831

medRxiv [Preprint]. 2025 May 7:2025.05.05.25326966. doi: 10.1101/2025.05.05.25326966.

ABSTRACT

Type 2 diabetes (T2D) is epidemiologically associated with a wide range of non-cardiovascular comorbidities, yet their shared etiology has not been fully elucidated. Leveraging eight non-overlapping mechanistic clusters of T2D genetic profiles, each representing distinct biological pathways, we investigate putative causal links between cluster-stratified T2D genetic predisposition and 21 non-cardiovascular comorbidities. Most of the identified putative causal effects are driven by distinct T2D genetic clusters. For example, the risk-increasing effects of T2D genetic predisposition on cataracts and erectile dysfunction are primarily attributed to obesity and glucose regulation mechanisms, respectively. When surveyed in populations across the globe, we observe opposing effect directions for depression, asthma and chronic obstructive pulmonary disease between populations. We identify a putative causal link between T2D genetic predisposition and osteoarthritis. To underscore the translational potential of our findings, we intersect high-confidence effector genes for osteoarthritis with targets of T2D-approved drugs and identify metformin as a potential candidate for drug repurposing in osteoarthritis.

PMID:40385452 | PMC:PMC12083600 | DOI:10.1101/2025.05.05.25326966

Drug Dev Res. 2025 May;86(3):e70101. doi: 10.1002/ddr.70101.

ABSTRACT

The global antibiotic resistance crisis demands innovative strategies targeting bacterial virulence rather than survival. Quorum sensing (QS), a key regulator of virulence and biofilm formation, offers a promising avenue to mitigate resistance by disarming pathogens without bactericidal pressure. This study investigates the repurposing of nitroimidazoles as anti-QS and anti-virulence agents at subminimum inhibitory concentrations (sub-MICs). In Silico analyses, including molecular docking and molecular dynamics (MD) simulations, were performed to investigate ligand-receptor interactions with structurally distinct Lux-type QS receptors and assess binding stability and conformational dynamics over time. In Vitro assays evaluated the effects of representative nitroimidazoles, metronidazole (MET) and secnidazole (SEC), on QS-controlled phenotypes, including violacein production in Chromobacterium violaceum and biofilm formation and protease activity in Pseudomonas aeruginosa, Acinetobacter baumannii, Salmonella enterica, and Proteus mirabilis. In Vivo efficacy was assessed using a murine infection model and HeLa cell invasion assays. Molecular docking revealed high-affinity binding to QS receptors, corroborating their mechanistic interference. Sub-MIC MET/SEC significantly suppressed violacein synthesis, biofilm biomass, and protease secretion in Gram-negative pathogens. Both compounds reduced bacterial invasiveness in HeLa cells and In Vivo protected mice from lethal P. aeruginosa infections. Crucially, nitroimidazoles attenuated virulence without affecting bacterial viability, preserving microbial ecology. These findings position nitroimidazoles as dual-function agents; antimicrobial at bactericidal doses and anti-virulence at sub-MICs. Their validated efficacy across In Silico, In Vitro, and In Vivo models underscores their potential as adjunctive therapies, bridging the gap between drug repurposing and next-generation anti-infective development.

PMID:40384051 | DOI:10.1002/ddr.70101

Integr Cancer Ther. 2025 Jan-Dec;24:15347354251339121. doi: 10.1177/15347354251339121. Epub 2025 May 18.

ABSTRACT

Chemotherapy-induced peripheral neuropathy (CIPN) has a markedly deleterious impact on a patient's quality of life. It manifests as pain, paresthesia, numbness, and weakness, particularly in the context of cisplatin (CDDP), a widely utilised chemotherapeutic agent renowned for its pronounced peripheral nerve toxicity. Trichosanthes kirilowii Maxim. (Cucurbitaceae, TK) and cucurbitacin D(CucD), its bioactive compound, have been demonstrated to possess anti-tumour, anti-inflammatory, and antioxidant properties. However, their potential to alleviate CIPN has not been fully exploredyet. The present study evaluated effectiveness of TK and CucD in mitigating CDDP-induced neuropathic pain using both cellular and animal models. CDDP, TK extracts (TKD and TKE), and CucD dose-dependently reduced viability and apoptosis of PC12 cells. Conversely, pre-treatment with TKD, TKE, and CucD exhibited significant protective effects against CDDP-induced cytotoxicity, preserving cell viability and morphology while enhancing neurite outgrowth. In vivo, administration of CDDP resulted in the development of mechanical allodynia and thermalhyperalgesia in rats. However, treatment with TKD and TKE led to a notable improvement in pain threshold and a reduction in hyperalgesia, while CucD demonstrated less pronounced effects. Although body weight was reduced in the CDDP-treated group, it was not significantly mitigated bytreatments. In conclusion, results of this study indicate that TKD, TKE, and CucD have the potential to alleviate CDDP-induced neuropathic pain by protecting against cell damage, promoting neuriteregeneration, and improving pain responses in animal models. Further investigation into TK and CucD as therapeutic options for managing CIPN is warranted.

PMID:40383960 | DOI:10.1177/15347354251339121

Carbohydr Polym. 2025 Jun 15;358:123478. doi: 10.1016/j.carbpol.2025.123478. Epub 2025 Mar 6.

ABSTRACT

Acute myeloid leukaemia (AML) accounts for 30 % of adult leukaemia cases, predominantly affecting individuals over 60. The standard "7 + 3" intensive chemotherapy regimen is unsuitable for many elderly patients, contributing to AML's poor prognosis. While progress in drug therapies has been made, breakthroughs remain limited, indication-specific, and slow to expand. Drug repurposing offers a faster route to therapy development, while nanocarrier encapsulation broadens the scope of viable drug candidates. Chlorpromazine (CPZ) is an antipsychotic which has been identified as a potential anti-leukaemic agent. Due to its ability to cross the blood-brain barrier, it is likely to cause central nervous system (CNS) effects. The drug-in-cyclodextrin-in-liposome (DCL) nanocarrier platform enables the formulation of CPZ encapsulated with cyclodextrins (CDs) such as HP-γ-CD, SBE-β-CD, and Sugammadex. The CD/CPZ formulations were equally, or more efficient than free CPZ in inducing AML cell death. Uptake of the DCL in AML cells quickly reached saturation, with minimal differences among formulations, except for SBE-β-CD. When injected intravenously in zebrafish larvae, the different DCLs did not differ in biodistribution, and no brain accumulation was observed at two days post-injection. These DCL-based CPZ formulations maintain anti-leukaemic activity, avoid CNS accumulation, and allow drug availability adjustments based on the included CD.

PMID:40383608 | DOI:10.1016/j.carbpol.2025.123478

Mol Neurobiol. 2025 May 17. doi: 10.1007/s12035-025-05047-5. Online ahead of print.

ABSTRACT

Disruption of the Wnt signaling pathway (WSP), a highly conserved pathway essential for growth and organ development, has been proven to play a role in the pathogenesis of Alzheimer's disease (AD). This study focused on repurposing the FDA-approved drug, Voglibose to target the DKK1-LRP6 site with the goal of upregulating WSP in in vitro as well as rodent model of AD. Based on our previous computational approach, Voglibose was evaluated for the DKK1 binding, neuroprotective effects were examined using SHSY5Y cells, while WSP activation was analyzed through RTPCR in the HEK293/LRP6 cell line. Rodent model of AD was developed using intracerebroventricular administration of Aβ25-35. Male Wistar rats were randomly assigned to receive oral doses of Voglibose (1 and 10 mg/kg) for 28 days, after which behavioral assessments, biochemical analyses, RT-PCR, and histopathological evaluations were conducted. Voglibose showed significant reduction in the DKK1 binding, neuroprotective property in SHSY5Y as well as activation of WSP in LRP6 overexpressed HEK293 cells. There was a significant decrease in the island latency in rats treated with lower dose (p < 0.01) and higher dose (p < 0.05) of Voglibose when compared to the disease control rats. Similarly, in the behavioral tests, Voglibose significantly improved cognition. The deposition of amyloid plaques was found to be considerably more in the disease control rats which got reduced in the treatment groups as observed in the histopathological slides stained with Congo red. Significant alterations in mRNA levels and protein expression of glycogen synthase kinase-β (GSK-3β), β-catenin (β-cat) was observed in rat brain homogenates indicating upregulation of WSP. In conclusion, Voglibose demonstrated significant neuroprotective potential in a cell line study and showed potential cognitive benefits in a rat model of AD. Furthermore, its ability to activate WSP highlights its immense potential as AD therapeutic to enhance memory and modulate key neuroprotective mechanisms.

PMID:40381169 | DOI:10.1007/s12035-025-05047-5

BMC Microbiol. 2025 May 16;25(1):299. doi: 10.1186/s12866-025-03973-x.

ABSTRACT

BACKGROUND: The urgent need for new antibacterial drugs has driven interest in repurposing therapies to combat Gram-positive biofilms and persisters. Fingolimod, an Food and Drug Administration (FDA)-approved drug for multiple sclerosis, shows bactericidal activity, particularly against Methicillin-resistant Staphylococcus aureus (MRSA) and biofilm-related infections. With a well-documented safety profile and strong translational potential, it aligns with World Health Organization's goals for antimicrobial repurposing. However, the action mode and mechanism of Fingolimod against gram-positive bacteria remain elusive.

METHODS: This study utilized clinical Staphylococcus aureus (S. aureus), Enterococcus faecalis (E. faecalis), Streptococcus agalactiae (S. agalactiae). And their susceptibility to Fingolimod and other antibiotics was tested via Minimum Inhibitory Concentration (MIC) assays. Biofilm inhibition and hemolytic activity were evaluated using crystal violet staining, Confocal Laser Scanning Microscopy (CLSM), and hemolysis assays, respectively, while the effect of phospholipids on Fingolimod efficacy was assessed with checkerboard assays. Membrane permeability and integrity were measured using SYTOX green staining and transmission electron microscopy. Whole-genome sequencing was performed on Fingolimod-resistant S. aureus isolates to identify Single Nucleotide Polymorphisms (SNPs) linked to resistance.

RESULTS: Our data indicated that Fingolimod exerted bactericidal activity against a wide spectrum of gram-positive bacteria, including S. aureus, E. faecalis, S. agalactiae. Moreover, Fingolimod could significantly eliminate the persisters, inhibit biofilm formation and eradicate in-vitro mature biofilms of S. aureus. The mechanism by which Fingolimod rapidly eradicated S. aureus involved a pH-dependent disruption of bacterial cell permeability and envelope integrity. Concomitantly, exogenous supplementation of phospholipids in the culture medium resulted in a dose-dependent increase in the MIC of Fingolimod. Specifically, the addition of 64 μg/mL of cardiolipin (CL) and phosphatidylethanolamine (PE) completely nullified the bactericidal activity of Fingolimod at a concentration of 4 times the MIC. After four months of Fingolimod exposure, the MIC values of S. aureus showed a slight increase, indicating that it is not prone to developing drug resistance.

CONCLUSION: Fingolimod exhibits bactericidal activity against diverse gram-positive bacteria, with remarkable effects on S. aureus (including MRSA), disrupting bacterial cell structural integrity in a pH-dependent way and eradicating biofilms and persisters of S. aureus.

PMID:40380090 | DOI:10.1186/s12866-025-03973-x

Int J Biol Macromol. 2025 May 14:144230. doi: 10.1016/j.ijbiomac.2025.144230. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD), the most common neurodegenerative disease in humans, has been a major medical challenge. Lactoferrin (Ltf) in salivary glands might be identified as a potential detectable biomarker in AD and a therapeutic target for AD. Pharmaceutical studies directly addressing this biomarker, though, are scarce. Using a computational strategy for drug repurposing, we explored the proximal neighborhood of Ltf by exploring its interactome and regulatory constellations. We aimed to focus on the discovery of potential therapeutic agents for AD. Based on extensive analytical evaluation comprising structural congruence scales, profiling disease clusters, pathway enrichment analyses as well as molecular docking, SPR, in vivo studies, and immunofluorescence assays, our research identified three candidate repurposed drugs: Lovastatin, SU-11652, and SB-239063. Taken together, these results highlight strong binding affinities of the drug candidates to Ltf. In vitro studies showed that such compounds decrease β-amyloid (Aβ) production by increasing the fluorescence signal emitted by Ltf in N2a-sw cells, and that they act by modulating the expression of amyloidogenic pathway-associated enzymes (BACE1 and APH1α). In addition, in vivo studies showed a concomitant reduction in the expression levels of amyloidogenic pathway-related enzymes (BACE1 or APH1α). Thus, computational studies have focused on Ltf interactions that may recommend drug repurposing strategies and options for AD.

PMID:40379164 | DOI:10.1016/j.ijbiomac.2025.144230

J Chem Inf Model. 2025 May 16. doi: 10.1021/acs.jcim.5c00435. Online ahead of print.

ABSTRACT

Drug repositioning, which identifies novel therapeutic applications for existing drugs, offers a cost-effective alternative to traditional drug development. However, effectively capturing the complex relationships between drugs and diseases remains challenging. We present HGCL-DR, a novel heterogeneous graph contrastive learning framework for drug repositioning that effectively integrates global and local feature representations through three key components. First, we introduce an improved heterogeneous graph contrastive learning approach to model drug-disease relationships. Second, for local feature extraction, we employ a bidirectional graph convolutional network with a subgraph generation strategy in the bipartite drug-disease association graph, while utilizing a graph diffusion process to capture long-range dependencies in drug-drug and disease-disease relation graphs. Third, for global feature extraction, we leverage contrastive learning in the heterogeneous graph to enhance embedding consistency across different feature spaces. Extensive experiments on four benchmark data sets using 10-fold cross-validation demonstrate that HGCL-DR consistently outperforms state-of-the-art baselines in both AUPR, AUROC, and F1-score metrics. Ablation studies confirm the significance of each proposed component, while case studies on Alzheimer's disease and breast neoplasms validate HGCL-DR's practical utility in identifying novel drug candidates. These results establish HGCL-DR as an effective approach for computational drug repositioning.

PMID:40377926 | DOI:10.1021/acs.jcim.5c00435

Tissue Barriers. 2025 May 16:2503523. doi: 10.1080/21688370.2025.2503523. Online ahead of print.

ABSTRACT

Vascular endothelial barrier disruption is a critical determinant of morbidity and mortality in sepsis. Whole blood represents a key source of paracrine signaling molecules inducing vascular endothelial barrier disruption in sepsis. This study analyzes whole-genome transcriptome data from sepsis patients' whole blood available in the NCBI GEO database to identify paracrine mediators of vascular endothelial barrier dysfunction, uncovering novel insights that may guide drug repositioning strategies. This study identifies the regulated expression of paracrine signaling molecules TFPI, MMP9, PROS1, JAG1, S1PR1, and S1PR5 which either disrupt or protect vascular endothelial barrier function in sepsis and could serve as potential targets for repositioning existing drugs. Specifically, TFPI (barrier protective), MMP9 (barrier destructive), PROS1 (barrier protective), and JAG1 (barrier destructive) are upregulated, while S1PR1 (barrier protective) and S1PR5 (barrier protective) are downregulated. Our observations highlight the importance of considering both protective and disruptive mediators in the development of therapeutic strategies to restore endothelial barrier integrity in septic patients. Identifying TFPI, MMP9, PROS1, JAG1, S1PR1, and S1PR5 as druggable paracrine regulators of vascular endothelial barrier function in sepsis could pave the way for precision medicine approaches, enabling personalized treatments that target specific mediators of endothelial barrier disruption to improve patient outcomes in sepsis.

PMID:40376886 | DOI:10.1080/21688370.2025.2503523

Trends Cancer. 2025 May 15:S2405-8033(25)00106-2. doi: 10.1016/j.trecan.2025.04.010. Online ahead of print.

ABSTRACT

The acknowledged relationship between metabolism and cancer retains important potential as a novel target in therapy. Reallocating glucose-lowering drugs (GLDs) in cancer treatment offers valuable perspectives for the ability of these molecules to regulate metabolism at cellular and systemic level. This comprehensive review addresses the therapeutic potential of the main antidiabetic classes of glucose-lowering drugs with emerging anticancer effects, such as metformin, rosiglitazone, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium/glucose cotransporter-2 inhibitors. The multifaceted actions of these drugs are explored, from in vitro evidence to clinical evidence as monotherapy or as a sparing agent with chemotherapy and immunotherapy. For each molecule, unconventional mechanisms, benefits, and limitations are dissected and possible concerns addressed, supporting evidence for the potential use of the drug in cancer.

PMID:40374399 | DOI:10.1016/j.trecan.2025.04.010

J Mol Graph Model. 2025 May 10;139:109076. doi: 10.1016/j.jmgm.2025.109076. Online ahead of print.

ABSTRACT

The hallmark of Alzheimer's disease (AD), a progressive neurodegenerative condition, is the buildup of amyloid-beta (Aβ) plaque, which is mainly caused by β-secretase 1 (BACE-1) activity. BACE-1 inhibition is a potentially effective treatment strategy to lower the progression of AD. In order to find possible BACE-1 inhibitors using a drug repurposing technique, this study uses an integrated computational approach that includes pharmacophore modelling, virtual screening, molecular docking, MM-GBSA, molecular dynamics (MD) simulations, in-silico ADMET profiling, and PBPK modelling. A pharmacophore model, was created with known BACE-1 inhibitors to enable virtual screening of both novel and FDA-approved chemical libraries. Top candidates with good free energy scores and strong binding affinities were found using molecular docking and MM-GBSA calculations. The stability of shortlisted Hits inside the BACE-1 active site was further validated using MD simulations, which showed that some of the important interactions were maintained across a period of 50ns. ADMET and PBPK studies predicted favorable pharmacokinetic and safety profiles for the shortlisted hits, particularly for B2 and B9. These findings identify potential candidates for future experimental validation, offering an inexpensive approach for identification of compounds as potential BACE-1 inhibitors.

PMID:40373679 | DOI:10.1016/j.jmgm.2025.109076

Protein Sci. 2025 Jun;34(6):e70156. doi: 10.1002/pro.70156.

ABSTRACT

Since the emergence of SARS-CoV-2 at the end of 2019, the virus has caused significant global health and economic disruptions. Despite the rapid development of antiviral vaccines and some approved treatments such as remdesivir and paxlovid, effective antiviral pharmacological treatments for COVID-19 patients remain limited. This study explores Nsp15, a 3'-uridylate-specific RNA endonuclease, which has a critical role in immune system evasion and hence in escaping the innate immune sensors. We conducted a comprehensive drug repurposing screen and identified 44 compounds that showed more than 55% inhibition of Nsp15 activity in a real-time fluorescence assay. A validation pipeline was employed to exclude unspecific interactions, and dose-response assays confirmed 29 compounds with an IC50 below 10 μM. Structural studies, including molecular docking and x-ray crystallography, revealed key interactions of identified inhibitors, such as TAS-103 and YM-155, with the Nsp15 active site and other critical regions. Our findings show that the identified compounds, particularly those retaining potency under different assay conditions, could serve as promising hits for developing Nsp15 inhibitors. Additionally, the study emphasizes the potential of combination therapies targeting multiple viral processes to enhance treatment efficacy and reduce the risk of drug resistance. This research contributes to the ongoing efforts to develop effective antiviral therapies for SARS-CoV-2 and possibly other coronaviruses.

PMID:40371758 | DOI:10.1002/pro.70156

Brief Bioinform. 2025 May 1;26(3):bbaf215. doi: 10.1093/bib/bbaf215.

ABSTRACT

Monkeypox (Mpox) is a major global human health threat after COVID-19. Its treatment becomes complicated with type-2 diabetes (T2D). It may happen due to the influence of both disease-causing common host key genes (cHKGs). Therefore, it is necessary to explore both disease-causing cHKGs to reveal their shared pathogenetic mechanisms and candidate drugs as their common treatments without adverse side effect. This study aimed to address these issues. At first, 3 transcriptomics datasets for each of Mpox and 6 T2D datasets were analyzed and found 52 common host differentially expressed genes (cHDEGs) that can separate both T2D and Mpox patients from the control samples. Then top-ranked six cHDEGs (HSP90AA1, B2M, IGF1R, ALD1HA1, ASS1, and HADHA) were detected as the T2D-causing cHKGs that are associated with the complexity of Mpox through the protein-protein interaction network analysis. Then common pathogenetic processes between T2D and Mpox were disclosed by cHKG-set enrichment analysis with biological processes, molecular functions, cellular components and Kyoto Encyclopedia of Genes and Genomes pathways, and regulatory network analysis with transcription factors and microRNAs. Finally, cHKG-guided top-ranked three drug molecules (tecovirimat, vindoline, and brincidofovir) were recommended as the repurposable common therapeutic agents for both Mpox and T2D by molecular docking. The absorption, distribution, metabolism, excretion, and toxicity and drug-likeness analysis of these drug molecules indicated their good pharmacokinetics properties. The 100-ns molecular dynamics simulation results (root mean square deviation, root mean square fluctuation, and molecular mechanics generalized born surface area) with the top-ranked three complexes ASS1-tecovirimat, ALDH1A1-vindoline, and B2M-brincidofovir exhibited good pharmacodynamics properties. Therefore, the results provided in this article might be important resources for diagnosis and therapies of Mpox patients who are also suffering from T2D.

PMID:40370100 | DOI:10.1093/bib/bbaf215

Indian J Microbiol. 2025 Mar;65(1):347-358. doi: 10.1007/s12088-024-01280-z. Epub 2024 Apr 18.

ABSTRACT

Antibiotic resistance in urinary tract infections (UTIs) is a growing concern due to extensive antibiotic use. The study explores a drug repurposing approach to find non-antibiotic drugs with antibacterial activity. In the present study, 8 strains of Pseudomonas spp. were used that were clinically isolated from UTI-infected patients. Amlodipine, a cardiovascular drug used in this study, has shown potential antimicrobial effect in reducing the various virulence factors, including swimming and twitching motility, biofilm, rhamnolipid, pyocyanin, and oxidative stress resistance against all the strains. Amlodipine exhibited the most potent antimicrobial activity with MIC in the range of 6.25 to 25 µg/ml. Significant inhibition in biofilm production was seen in the range of 45.75 to 76.70%. A maximum decrease of 54.66% and 59.45% in swimming and twitching motility was observed, respectively. Maximum inhibition of 65.87% of pyocyanin pigment was observed with the effect of amlodipine. Moreover, a significant decrease in rhamnolipids production observed after amlodipine treatment was between 16.5 and 0.001 mg/ml as compared to the control. All bacterial strains exhibited leakage of proteins and nucleic acids from their cell membranes when exposed to amlodipine which suggests the damage of the structural integrity. In conclusion, amlodipine exhibited good antimicrobial activity and can be used as a potential candidate to be repurposed for the treatment of urinary tract infections.

PMID:40371041 | PMC:PMC12069773 | DOI:10.1007/s12088-024-01280-z