Molecules. 2025 Apr 24;30(9):1897. doi: 10.3390/molecules30091897.

ABSTRACT

Crohn's disease is an inflammatory bowel disease (IBD) that currently lacks satisfactory treatment options. Therefore, new targets for new drugs are urgently needed to combat this disease. In the present study, we investigated the transcriptomics-based mRNA expression of intestinal biopsies from patients with Crohn's disease. We compared the mRNA expression profiles of the ileum and colon of patients with those of healthy individuals. A total of 72 genes in the ileum and 33 genes in the colon were differentially regulated. Among these, six genes were overexpressed in both tissues, including IL1B, TCL1A, HCAR3, IGHG1, S100AB, and OSM. We further focused on OSM/oncostatin M. To confirm the responsiveness of intestinal tissues from patients with Crohn's disease to oncostatin M inhibition, we examined the expression of the oncostatin M using immunohistochemistry in patient biopsies as well as in kindlin-1-/- and kindlin-2-/- knockout mice, which exhibit an inflammatory bowel disease (IBD) phenotype, and found strong oncostatin M expression in all samples examined. Next, we conducted a drug-repurposing study using the supercomputer MOGON and bioinformatic methods. A total of 13 candidate compounds out of 1577 FDA-approved drugs were identified by PyRx-based virtual drug screening and AutoDock-based molecular docking. Their lowest binding energies (LBEs) ranged from -10.46 (±0.08) to -8.77 (±0.08) kcal/mol, and their predicted inhibition constants (pKi) ranged from 21.62 (±2.97) to 373.78 (±36.78) nM. Ecamsule has an interesting stereostructure with two C2-symmetric enantiomers (1S,4R-1'S,4'R and 1R,4S-1'R,4'S) (1a and 1b) and one meso diastereomer (1S,4R-1'R,4'S) (1c). These three stereoisomers showed strong, albeit differing, binding affinities in molecular docking. As examined by nuclear magnetic resonance and polarimetry, the 1S,4R-1'S,4'R isomer was the stereoisomer present in our commercially available preparations used for microscale thermophoresis. Ecamsule (1a) was chosen for in vitro validation using recombinant oncostatin M and microscale thermophoresis. Considerable dissociation constants were obtained for ecamsule after three repetitions with a Kd value of 11.36 ± 2.83 µM. Subsequently, we evaluated, by qRT-PCR, the efficacy of ecamsule (1a) as a potential drug that could prevent oncostatin M activation by inhibiting downstream inflammatory marker genes (IL6, TNFA, and CXCL11). In conclusion, we have identified oncostatin M as a promising new drug target for Crohn's disease through transcriptomics and ecamsule as a potential new drug candidate for Crohn's disease through a drug-repurposing approach both in silico and in vitro.

PMID:40363705 | DOI:10.3390/molecules30091897

Int J Mol Sci. 2025 May 7;26(9):4453. doi: 10.3390/ijms26094453.

ABSTRACT

Parkinson's disease (PD) is a complex neurodegenerative disorder lacking effective disease-modifying treatments. In this study, we integrated large-scale protein-protein interaction networks with a multi-modal graph neural network (GNN) to identify and prioritize multi-target drug repurposing candidates for PD. Network analysis and advanced clustering methods delineated functional modules, and a novel Functional Centrality Index was employed to pinpoint key nodes within the PD interactome. The GNN model, incorporating molecular descriptors, network topology, and uncertainty quantification, predicted candidate drugs that simultaneously target critical proteins implicated in lysosomal dysfunction, mitochondrial impairment, synaptic disruption, and neuroinflammation. Among the top hits were compounds such as dithiazanine, ceftolozane, DL-α-tocopherol, bromisoval, imidurea, medronic acid, and modufolin. These findings provide mechanistic insights into PD pathology and demonstrate that a polypharmacology approach can reveal repurposing opportunities for existing drugs. Our results highlight the potential of network-based deep learning frameworks to accelerate the discovery of multi-target therapies for PD and other multifactorial neurodegenerative diseases.

PMID:40362692 | DOI:10.3390/ijms26094453

Int J Mol Sci. 2025 Apr 25;26(9):4079. doi: 10.3390/ijms26094079.

ABSTRACT

Thiol-containing drugs may interact with a region of tropomyosin receptor kinase A (TrkA), potentially inhibiting its activation by nerve growth factor (NGF). This action has been linked to potential analgesic activities. Here, we describe the ability of erdosteine, a thiolic compound classified as a mucolytic agent, to bind to the TrkA receptor sequence in silico and its in vitro effects on TrkA activation induced by NGF in cultured human neuroblastoma cells. Our results show that erdosteine and its metabolite, Met-1, bind to the TrkA receptor pocket, involving the primary TrkA residues Glu331, Arg347, His298, and His297. Furthermore, Met-1 has the ability to reduce the disulfide bridge between Cys300 and Cys345 of TrkA. In vitro measurement of TrkA autophosphorylation following NGF activation confirmed that erdosteine and Met-1 interfere with NGF-induced TrkA activation, leading to a consequent loss of the molecular recognition and spatial reorganization necessary for the induction of the autophosphorylation process. This effect was inhibited by low millimolar concentrations of the two compounds, reaching a maximal inhibition (around 40%) after 24 h of exposure to 1 mM erdosteine, and then plateauing. These findings suggest that erdosteine can act as a TrkA antagonist, thus indicating that this drug may have potential as an analgesic via a novel non-opioid mechanism of action operating through NGF signaling inhibition at the level of TrkA.

PMID:40362318 | DOI:10.3390/ijms26094079

Int J Mol Sci. 2025 Apr 22;26(9):3936. doi: 10.3390/ijms26093936.

ABSTRACT

The high heterogeneity between patients can complicate the diagnosis and treatment of pancreatic ductal adenocarcinoma (PDAC). Here, we explored the association of universally differentially expressed genes (UDEGs) with resistance to chemotherapy and immunotherapy in the context of pancreatic cancer. In this work, sixteen up-regulated and three down-regulated genes that were dysregulated in more than 85% of 102 paired and 5% of 521 unpaired PDAC samples were identified and defined as UDEGs. A single-cell level analysis further validated the high expression levels of the up-UDEGs and the low levels of the down-UDEGs in cancer-related ductal cells, which could represent the malignant changes seen in pancreatic cancer. Based on a drug sensitivity analysis, we found that ANLN, GPRC5A and SERPINB5 are closely related to the resistance mechanism of PDAC, and their high expression predicted worse survival for PDAC patients. This suggests that targeting these genes could be a potential way to reduce drug resistance and improve survival. Based on the immune infiltration analysis, the abnormal expression of the UDEGs was found to be related to the formation of an immunosuppressive tumor microenvironment. In conclusion, these UDEGs are common features of PDAC and could be involved in the resistance of pancreatic cancer and might serve as novel drug targets to guide research into drug repurposing.

PMID:40362181 | DOI:10.3390/ijms26093936

Cancers (Basel). 2025 Apr 27;17(9):1470. doi: 10.3390/cancers17091470.

ABSTRACT

BACKGROUND/OBJECTIVES: Colorectal cancer (CRC) is a significant global health issue with rising incidence and mortality rates. In oncology, drug repurposing has emerged as a promising therapeutic strategy in conjunction with conventional treatments. This study aimed to evaluate the potential of repurposing propranolol (PRO), a beta blocker, for the treatment of CRC cell lines (HCT-116 and HT-29), both as a monotherapy and in combination with capecitabine (CAP).

METHODS: Effects of mono- and combination therapies on viability, combination index, morphology, and cell death induction of CRC cells were assessed. Transcriptome analysis of HT-29 cells was performed using RNA sequencing. Metabolite profiling was conducted, and changes in biochemical parameters were evaluated using flow cytometry and biochemical analyses.

RESULTS: The combination index showed that HT-29 cells were the most responsive to the combined treatment, even with PIK3CA, B-RAF (V600E), and TP53 mutations. Moreover, ferroptosis was synergistically activated in the combined group of HT-29 in comparison to control. Furthermore, we observed an increase in OXPHOS metabolites, along with elevated intracellular and mitochondrial ROS, disruption of mitochondrial membrane potential, and greater levels of malondialdehyde (MDA) in the HT-29 combined group, which are the features of ferroptosis. Furthermore, ferroptosis induction was coupled with necroptosis, as indicated by RNA-sequencing data. Combination therapy inhibited cell migration and enhanced the immune response of HT-29 cells.

CONCLUSIONS: These findings suggest that PRO is promising as a potential adjuvant therapy in combination with CAP for the treatment of CRC. Only HT-29 cells with the B-RAF (V600E) mutation showed promising findings in this study.

PMID:40361395 | DOI:10.3390/cancers17091470

Cancers (Basel). 2025 Apr 24;17(9):1430. doi: 10.3390/cancers17091430.

ABSTRACT

Background: Chronic nicotine exposure drives head and neck cancer (HNC) progression, yet its molecular mechanisms remain underexplored. This study examines nicotine-induced transcriptomic changes and potential therapies via drug repurposing. Methods: HNC cell lines (OECM1, SAS, and CGHNC9) were exposed to an IC30 nicotine dose for three months to model chronic exposure in habitual smokers. Transcriptomic profiling of these sublines was integrated with TCGA-HNSC patient data. Differentially expressed genes (DEGs) underwent functional pathway enrichment analysis. Drug repurposing was conducted using gene-drug correlation analysis across GDSC, CTRP, and PRISM databases. Results: Transcriptomic analysis identified 1223 DEGs in nicotine-exposed HNC cells, and integration with TCGA-HNSC data defined a Nic-HNC gene set of 168 genes: 149 oncogenes and 19 tumor suppressors, with 36 oncogenes overexpressed in heavy smokers. Pathway analysis revealed the upregulation of oncogenic signaling, such as PI3K-AKT, alongside the suppression of immune regulation and metabolic reprogramming. Drug repurposing identified five compounds-AZD1332, JAK-8517, NU7441, BRD-K30748066, and neopeltolide-with the first two exhibiting the strongest inverse correlations with nicotine-induced oncogenes in heavy smokers, highlighting their potential as targeted therapies for tobacco-associated HNC. Conclusions: This study comprehensively characterizes nicotine-driven molecular dysregulation in HNC and proposes AZD1332 and JAK-8517 as promising therapeutic candidates through drug repurposing. These insights advance our understanding of nicotine's oncogenic role and provide a foundation for translational research to develop targeted interventions for tobacco-associated HNC.

PMID:40361356 | DOI:10.3390/cancers17091430

Mycopathologia. 2025 May 14;190(3):41. doi: 10.1007/s11046-025-00948-4.

ABSTRACT

BACKGROUND: Candida auris is a significant clinical concern due to its ability to cause outbreaks in healthcare settings and its common resistance to current treatments. This highlights the need for alternative therapies. Drug repurposing offers a promising approach, and the combination of pentamidine (antiprotozoal) and auranofin (anti-rheumatic) has shown potential antifungal activity against Candida species, including C. auris. This study aimed to evaluate the antifungal activity of pentamidine and auranofin, both individually and in combination, against C. auris.

METHODS: Minimum Inhibitory Concentrations (MICs) were determined following CLSI guidelines, and drug interactions were assessed using the checkerboard microdilution method. Additional evaluations included growth inhibition, antibiofilm activity, cell damage, sorbitol protection, and efflux pump inhibition. Nucleotide leakage and cell membrane permeability were analyzed using biochemical assays. In vivo efficacy was tested using a Tenebrio molitor larvae model infected with C. auris.

RESULTS: The MICs of pentamidine against C. auris ranged from 16 to 128 μg/mL, showing fungicidal activity. The combination with auranofin had a synergistic effect (FICI: 0.37) and exhibited a fungistatic effect in growth inhibition assays. Auranofin was most effective at inhibiting biofilm formation. Pentamidine impaired mitochondrial function, leading to cellular respiration issues and membrane damage. Efflux pump assays indicated activation by both drugs, potentially influencing resistance. In vivo tests showed both drugs significantly improved survival rates in infected larvae compared to fluconazole.

CONCLUSION: In conclusion, pentamidine and auranofin, either individually or in combination, are promising treatments for C. auris and warrant further research into optimal dosing and combination strategies.

PMID:40360957 | DOI:10.1007/s11046-025-00948-4

Sci Rep. 2025 May 13;15(1):16510. doi: 10.1038/s41598-025-01574-2.

ABSTRACT

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite advances in the treatment of ALL, high disease recurrence and the impact of chemical toxicity on patients' quality of life persist. Drug repositioning has been proven to have antitumor and anti-inflammatory properties in leukemia. This study investigated the effects of metformin and chloroquine on the efficacy of cytarabine in NALM-6 cells. The growth inhibitory effects of metformin (Met) and chloroquine (CQ) on the response of NALM-6 cells to cytarabine (AraC) were determined via the MTT assay. To test the regeneration potential, a colony formation assay was performed. Apoptosis and cell cycle analyses were executed via flow cytometry. Oxidative stress markers and antioxidant activity were measured. Gene expression analysis and protein measurement of apoptotic and signaling pathways were performed. The administration of metformin and chloroquine increased the efficacy of cytarabine in suppressing NALM-6 cells, leading to decreased colony formation, increased apoptosis, and G1 phase cell cycle arrest. These effects are mediated by the upregulation of TP53, CASP3 and CASP8 genes and the reduction in BCL-2, NRAS and KRAS genes. Our data suggest that the combination of AraC with Met and CQ may be an effective approach for the treatment of B-ALL.

PMID:40360710 | DOI:10.1038/s41598-025-01574-2

Comput Biol Med. 2025 May 12;192(Pt B):110249. doi: 10.1016/j.compbiomed.2025.110249. Online ahead of print.

ABSTRACT

MOTIVATION: Accurately predicting drug-target interactions (DTIs) is critical for accelerating drug discovery, repositioning, and development. Traditional experimental methods are often expensive and time-consuming, emphasizing the need for efficient computational models to streamline these processes. To address this challenge, we developed MiRAGE-DTI, a novel computational framework that integrates diverse drug and target similarity measures with robust machine learning techniques to achieve superior predictive accuracy.

RESULTS: MiRAGE-DTI introduces a novel framework that integrates structural, functional, and interaction-based features into a unified model. Leveraging the strengths of Random Forest classifiers, MiRAGE-DTI ensures robust and interpretable predictions while addressing challenges such as class imbalance and data variability. Comprehensive evaluations across multiple benchmark datasets, including GPCR, IC, NR, and Enzyme, reveal that MiRAGE-DTI consistently outperforms state-of-the-art algorithms such as DTI-CNN, GCNMDA, MVGCN, MMGCN, GraphCDA, DTINet, and MIDTI. It achieves significant improvements in key metrics such as AUROC, AUPR, and accuracy. To validate its predictions, molecular docking studies were conducted, highlighting strong binding affinities for key drug-target interactions, including Oxandrolone-PGR and Metyrapone-CYP2E1, which demonstrate high therapeutic potential. Beyond predictive accuracy, MiRAGE-DTI has practical implications in drug repositioning and personalized medicine, as well as the potential to streamline preclinical workflows. Its ability to uncover novel drug-target relationships enhances the understanding of molecular mechanisms underlying diseases, paving the way for innovative therapeutic strategies. Furthermore, by predicting off-target interactions and potential side effects, MiRAGE-DTI contributes to improving drug safety profiles and regulatory evaluations.

CONCLUSION: MiRAGE-DTI represents a versatile and powerful tool for advancing drug discovery and development. Its ability to identify novel therapeutic opportunities, repurpose existing drugs, and enable precision medicine highlights its transformative potential in tackling unmet medical needs. The framework's robust performance, validated predictions, and wide-ranging practical applications position MiRAGE-DTI as a critical resource for modern drug discovery.

PMID:40359678 | DOI:10.1016/j.compbiomed.2025.110249

Front Pharmacol. 2025 Apr 28;16:1565628. doi: 10.3389/fphar.2025.1565628. eCollection 2025.

ABSTRACT

INTRODUCTION: The escalating prevalence of diabetes and non-alcoholic fatty liver disease (NAFLD) has intensified the search for effective therapeutic interventions. The current study investigates the potential of ondansetron, a Food and Drug Administration (FDA)-approved drug for conditions like nausea and vomiting, as a novel treatment option for these metabolic disorders.

METHODS: A multifaceted approach, encompassing computational analyses, in vitro enzyme inhibition assays, and in vivo experiments in a high-fat diet (HFD)-induced disease model in rats were employed.

RESULTS: Computational studies, including pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulations, revealed the strong binding affinity of ondansetron to the allosteric site of protein tyrosine phosphatase 1B (PTP1B), a key regulator of insulin and lipid homeostasis. The in vitro enzyme inhibition assay further confirmed ondansetron's ability to directly inhibit PTP1B activity. Animal experiments demonstrated ondansetron's antihyperglycemic effects, reducing blood glucose levels and improving insulin sensitivity in HFD-fed rats. The drug also exhibited hepatoprotective properties, mitigating liver damage and improving tissue architecture. Additionally, ondansetron's anti-inflammatory and antioxidant activities were evident in its ability to reduce pro-inflammatory markers and oxidative stress in the liver.

DISCUSSION: These therapeutic effects position ondansetron as a promising candidate for further investigation in clinical settings for the treatment of diabetes and NAFLD and, hence, support the use of the drug repurposing approach for addressing the growing burden of metabolic diseases.

PMID:40356976 | PMC:PMC12066537 | DOI:10.3389/fphar.2025.1565628

Clin Exp Pharmacol Physiol. 2025 Jul;52(7):e70031. doi: 10.1111/1440-1681.70031.

ABSTRACT

Sepsis is a life-threatening disease caused by the dysregulation of the immune response. It is important to identify influential genes modulating the immune response in sepsis. In this study, we used P-NET, a biologically informed explainable artificial intelligence model, to evaluate the gene importance for sepsis. About 688 important genes were identified, and these genes were enriched in pathways involved in inflammation and immune regulation, such as the PI3K-Akt signalling pathway, necroptosis and the NF-κB signalling pathway. We further selected differentially expressed genes both at bulk and single-cell levels and found TIMP1, GSTO1 and MYL6 exhibited significant different expressions in multiple cell types. Moreover, the expression levels of these 3 genes were correlated with the abundance of important immune cells, such as M-MDSC cells. Further analysis demonstrated that these three genes were highly expressed in sepsis patients with worse outcomes, such as severe, non-survived and shock sepsis patients. Using a drug repositioning strategy, we found navitoclax, curcumin and rotenone could down-regulate and bind to these genes. In conclusion, TIMP1, GSTO1 and MYL6 may serve as promising biomarkers and targets for sepsis treatment.

PMID:40356040 | DOI:10.1111/1440-1681.70031

Sci Rep. 2025 May 12;15(1):16440. doi: 10.1038/s41598-025-00024-3.

ABSTRACT

Deforestation, urbanization, and climate change have significantly increased the risk of zoonotic diseases. Nipah virus (NiV) of Paramyxoviridae family and Henipavirus genus is transmitted by Pteropus bats. Climate-induced changes in bat migration patterns and food availability enhances the virus's adaptability, in turn increasing the potential for transmission and outbreak risk. NiV infection has high human fatality rate. With no antiviral drugs or vaccines available, exploring the complex machinery involved in viral RNA synthesis presents a promising target for therapy. Drug repurposing provides a fast-track approach by identifying existing drugs with potential to target NiV RNA-dependent RNA polymerase (L), bypassing the time-consuming process of developing novel compounds. To facilitate this, we developed an attention-based deep learning model that utilizes pharmacophore properties of the active sites and their binding efficacy with NiV L protein. Around 500 FDA-approved drugs were filtered and assessed for their ability to bind NiV L protein. Compared to the control Remdesivir, we identified Cangrelor, an antiplatelet drug for cardiovascular diseases, with stronger binding affinity to NiV L (glide score of -12.30 kcal/mol). Molecular dynamics simulations further revealed stable binding (RMSD of 3.54 Å) and a post-MD binding energy of -181.84 kcal/mol. The strong binding of Cangrelor is illustrated through trajectory analysis, principal component analysis, and solvent accessible surface area, further confirming the stable interaction with the active site of NiV RdRp. Cangrelor can interact with NiV L protein and may potentially interfere with its replication. These findings suggest that Cangrelor will be a potential drug candidate that can effectively interact with the NiV L protein and potentially disrupt the viral replication. Further in vivo studies are warranted to explore its potential as a repurposable antiviral drug.

PMID:40355437 | DOI:10.1038/s41598-025-00024-3

Cancer Res Commun. 2025 May 12. doi: 10.1158/2767-9764.CRC-24-0433. Online ahead of print.

ABSTRACT

Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy is the main treatment for muscle-invasive bladder cancer (MIBC). However, low survival rates highlight the necessity for new therapeutic strategies. Drug repurposing has emerged as a promising approach in cancer treatment, with various studies proposing the use of existing drugs for the treatment of bladder cancer (BC). In this context, we previously established an in silico repurposing strategy using patient -omics signatures, identifying drugs and compounds with the potential to reverse non-muscle invasive BC (NMIBC) to less aggressive subtypes. In the present study, we expanded our in silico approach to verify a list of compounds with potential anti-tumor activity against MIBC. We investigated the efficacy of the predicted candidates in a group of different BC cell lines, including NMIBC and MIBC. The most potent compound for decreasing cell viability was amiodarone, an anti-arrhythmic drug widely used in the field of cardiology. Amiodarone reduced cell proliferation and colony formation capacity, with a stronger effect on the most aggressive invasive models, validating our repurposing pipeline. The drug additionally induced cell death and inhibited the activity of mTOR and its target protein S6, suggesting that the anti-cancer effect of the drug is in part mediated by inhibition of the mTOR signaling pathway. Furthermore, the administration of amiodarone in a xenograft MIBC mouse model reduced tumor growth without inducing toxicity. Altogether, we demonstrated that amiodarone is a potential repurposed drug for BC, which might be especially effective in MIBC.

PMID:40353763 | DOI:10.1158/2767-9764.CRC-24-0433

Protein Pept Lett. 2025 May 8. doi: 10.2174/0109298665366911250416113831. Online ahead of print.

ABSTRACT

BACKGROUND: COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly pathogenic human coronavirus (CoV). For the treatment of COVID-19, various drugs, ayurvedic formulations, used for other diseases, were repurposed. Ayurveda and yoga exhibited a pivotal role in the treatment of COVID-19. Various medicinal plants, including garlic, tulsi, clove, cinnamon, ginger, black pepper, and turmeric, are recommended for the prevention of COVID-19 as immunity boosters along with their antiviral property.

OBJECTIVE: In view of the drug repurposing approach, the present work has been initiated with the broader objectives of screening and identification of phytoconstituents of Indian spices against targets, namely furin, 3C-like protease (3CL-PRO), NSP-9 RNA binding protein, papain-like protease, RNA dependent RNA polymerase (RDRP), spike protein concerned with life cycle of SARS-CoV-2 using in-silico tools.

METHOD: The phytoconstituents of Indian spices were screened for interaction with several targets using a molecular docking approach with the help of Discovery Studio 4.5 software. Furthermore, the pharmacokinetic analyses of selected ligands using ADMET and Lipinski's rule of five were also performed.

RESULT: In the present study, more than 35 active phytoconstituents of Indian spices were screened for interaction with several identified targets of Covid-19 using a molecular docking approach. The ligands, namely morin, gingerol, myristic acid, quercetin, gallic acid, octacosanal, and alliin were found to be the top interacting ligands with the targets analyzed.

CONCLUSION: Based on the present in-silico finding, the active components of spices could be considered for drug-lead compounds against COVID-19.

PMID:40353411 | DOI:10.2174/0109298665366911250416113831

Anim Cells Syst (Seoul). 2025 May 8;29(1):325-338. doi: 10.1080/19768354.2025.2489389. eCollection 2025.

ABSTRACT

Yes-associated protein (YAP), a key co-transcription factor of the Hippo pathway, is a promising drug target for cancer therapy due to its critical role in promoting cell proliferation, survival, and tumor progression when dysregulated. While most Hippo pathway-targeting drugs focus on disrupting TEAD-YAP interactions or modulating the MST or LATS kinase cascade, new approaches are needed to identify small molecules that regulate YAP activity. In this study, we conducted high-throughput screening of FDA-approved drugs to discover potential YAP modulators. Using a NanoBiT-based system, which enables real-time and quantitative measurement of protein interactions, combined with phenotype-based assays in EGFP-YAP-expressing cells, we identified compounds that activate or inhibit YAP function. Among the identified YAP regulators, the microtubule destabilizer vinorelbine promoted YAP nuclear localization and transcriptional activation, while the antipsychotic drug thioridazine enhanced YAP phosphorylation at Ser127, resulting in its cytoplasmic retention and reduced transcriptional activity, effectively suppressing cancer cell growth. These findings demonstrate the potential of FDA-approved drugs in modulating YAP activity and present a novel screening strategy for developing YAP-targeting therapeutics. Furthermore, this approach can be extended to identify modulators of other signaling pathways, advancing drug discovery for a wide range of diseases.

PMID:40353256 | PMC:PMC12064127 | DOI:10.1080/19768354.2025.2489389

Narra J. 2025 Apr;5(1):e1130. doi: 10.52225/narra.v5i1.1130. Epub 2025 Jan 17.

ABSTRACT

Tuberculosis (TB) remains a significant and deadly infection among pulmonary diseases caused by Mycobacterium tuberculosis, a highly adaptive bacterium. The ability of M. tuberculosis to evade certain drugs has been linked to its unique structure, particularly in the cell envelope, where the Ag85 complex proteins play an essential role in this part. The aim of this study was to utilize a drug repurposing strategy targeting the Ag85 complex proteins. This study utilized a computational approach with 120 selected drugs experimentally identified to inhibit Tuberculosis. A virtual screening molecular docking with Autodock Vina was used to filter the compounds and identify the strong binders to the Ag85 Complex. Molecular dynamics simulations employed the Gromacs Packages to evaluate the stability of each complex, including root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (RoG). Additionally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessments were conducted to gather more information about the drug-likeness of each hit compound. Three compounds, selamectin, imatinib, and eltrombopag were selected as potential drugs repurposed to inhibit the activity of the Ag85 complex enzyme, with binding affinities ranging between -10.560 kcal/mol and -11.422 kcal/mol. The MD simulation within 100 ns (3 replicas) showed that the average RMSD of each Ag85A complex was 0.15 nm-0.16 nm, RMSF was 0.09 nm-0.10 nm, and RoG was 1.80 nm-1.81 nm. For Ag85B, the average RMSD was 1.79 nm-1.80 nm, RMSF was 0.08 nm-0.09 nm, and RoG was 1.79 nm-1.80 nm. Then, for Ag85C, the mean RMSD was 0.16 nm-0.18 nm, RMSF was 0.09, and RoG was 1.77 nm. The study highlights that these promising results demonstrate the potential of some repurposed drugs in combating the Ag85 complex.

PMID:40352212 | PMC:PMC12059857 | DOI:10.52225/narra.v5i1.1130

Antiviral Res. 2025 May 8:106172. doi: 10.1016/j.antiviral.2025.106172. Online ahead of print.

ABSTRACT

The burden of dengue on human health has dramatically increased in recent years, underscoring the urgent need for effective therapeutic interventions. Despite decades of research since the discovery of the dengue virus, no specific antiviral treatments are available and strategies to reliably prevent severe disease remain limited. Direct-acting antivirals against dengue are under active investigation but have shown limited efficacy to date. An underappreciated Achille's heal of the virus is its dependence on host factors for infection and pathogenesis, each of which presents a potential avenue for therapeutic intervention. We and others have demonstrated that dengue virus relies on multiple host kinases, some of which are already targeted by clinically approved inhibitors. These offer drug repurposing opportunities for host-directed dengue treatment. Here, we summarize findings on the role of kinases in dengue infection and disease and highlight potential kinase targets for the development of innovative host-directed therapeutics.

PMID:40348023 | DOI:10.1016/j.antiviral.2025.106172

Comput Biol Med. 2025 May 9;192(Pt B):110203. doi: 10.1016/j.compbiomed.2025.110203. Online ahead of print.

ABSTRACT

Pre-eclampsia (PE) is a severe vascular disorder during pregnancy, significantly affecting maternal and fetal health worldwide. However, the exact molecular mechanism of its pathophysiology remains unclear, highlighting the need for reliable early diagnostic methods. Our primary aim of this study was to identify key genes (KGs) that may affect the outcome of patients with PE via integrated bioinformatics analysis. We analysed a gene expression dataset from the national center for biotechnology information (NCBI) sequence read archive (SRA) database and performed standard preprocessing steps, including quality assessment, trimming, genome alignment, and feature counts. Following this, normalization and differentially expressed genes (DEGs) were performed using Deseq2, which identified 781 DEGs were identified comprising 457 upregulated and 324 downregulated genes. Identified DEGs were significantly enriched in the cytokine interaction pathway and cellular calcium ion homeostasis. PPI network analysis revealed eight KGs (CXCL8, GAPDH, MMP9, SPP1, PTGS2, LEP, FGF7, and FGF10). These KGs were further found to be regulated by ten transcription factors (TFs), among which NF-kB1 and RELA consistently interact with all the KGs, and four microRNAs (miRNAs) such as hsa-mir-335-5p, has-mir-16a-5p, has-let-7b-5p, and has-mir-204-5p. The least absolute shrinkage and selection operator (LASSO) regression with 10-fold cross-validation (CV) confirmed all eight KGs may act as potential biomarkers based on their coefficients. Among these, GAPDH, SPP1, FGF7, and FGF10 emerged as novel biomarkers. Additionally, receiver operating characteristic (ROC) curve analysis for these novel biomarkers showed an area under the curve (AUC) of 0.869, demonstrating strong discriminatory power between the healthy and EOPE groups. The drug-gene interaction was performed by DrugMap database revealed an important interaction of GAPDH and FGF7 with FDA-approved drugs, indicating their therapeutic significance in PE. This analysis also facilitates drug repurposing for PE treatment.

PMID:40347801 | DOI:10.1016/j.compbiomed.2025.110203

Pharmacotherapy. 2025 May 10. doi: 10.1002/phar.70028. Online ahead of print.

ABSTRACT

BACKGROUND: Oxaliplatin-induced peripheral neuropathy (OIPN) is a major clinical challenge because it leads to discontinuation of chemotherapy. Omeprazole, a proton pump inhibitor (PPI), has been shown to prevent OIPN in a rat model. Therefore, we aimed to test whether the concomitant use of a PPI reduces oxaliplatin discontinuation due to OIPN.

METHODS: This retrospective study used data from 1015 patients who started treatment with oxaliplatin and evaluated two cohorts (PPI vs. non-PPI). The primary outcome measure was oxaliplatin discontinuation due to OIPN. A Kaplan-Meier curve was generated for cumulative doses and evaluated using the log-rank test and Cox proportional hazards analysis.

RESULTS: The log-rank test showed that the number of patients who discontinued oxaliplatin due to OIPN was significantly lower in the PPI group (p = 0.0264). Cox proportional hazards analysis incorporated and analyzed factors previously reported as potentially affecting neuropathy (sex, age, use of PPIs, calcium channel antagonists, opioids and adjuvant analgesics, and the CAPOX [capecitabine + oxaliplatin] regimen). The analysis suggested that the concomitant use of PPIs was a factor in reducing oxaliplatin discontinuation (adjusted hazard ratio [HR] = 0.568, 95% confidence interval [CI], 0.344-0.937, p = 0.0269). Since there were significant differences in some patient demographics between the two groups, propensity score matching was performed to align the patient demographics and then reanalyzed. After propensity score matching, the same analysis as above showed that oxaliplatin discontinuation due to OIPN was significantly less common in the PPI group (p = 0.0081); cox proportional hazards analysis showed that PPI use was a factor that significantly reduced oxaliplatin discontinuation due to OIPN (adjusted HR = 0.478, 95% CI, 0.273-0.836, p = 0.0096).

CONCLUSIONS: These results suggest that concomitant PPI use may reduce oxaliplatin discontinuation due to OIPN in patients receiving oxaliplatin.

PMID:40347077 | DOI:10.1002/phar.70028

Chem Biol Drug Des. 2025 May;105(5):e70122. doi: 10.1111/cbdd.70122.

ABSTRACT

Carprofen, a nonsteroidal anti-inflammatory drug (NSAID) derived from propanoic acid, is known for its analgesic and antipyretic properties. Although it has long been employed in veterinary medicine as an anti-inflammatory agent, its use in humans was discontinued shortly after its market launch due to costly raw materials, complex synthesis, and labor-intensive production processes-factors that made it less competitive compared with other NSAIDs. Despite this, the carprofen molecule remains a subject of significant scientific interest. Recent advancements in its synthesis have introduced simplified and more cost-effective methods, reigniting its potential for both novel applications and drug repurposing. Exciting new research is exploring carprofen's broader therapeutic possibilities, extending beyond its original anti-inflammatory role. Studies are investigating its efficacy in antimicrobial therapy-including antibiofilm, anticancer, antiviral, and anti-Alzheimer's applications-opening doors to a wealth of untapped possibilities. This review delves into these emerging areas, highlighting how carprofen's molecular structure and derivatives can be leveraged to expand its therapeutic reach. The literature review was conducted using four databases: Web of Science, ScienceDirect, Scopus, Embase, and Reaxys. The review focused on English-language original research and review articles, examining carprofen and its derivatives in terms of their synthesis methods as well as their use as small molecules in various therapeutic applications, both human and veterinary. With ongoing research pushing the boundaries of its potential, carprofen remains a promising candidate for innovation in drug development and treatment strategies.

PMID:40346933 | DOI:10.1111/cbdd.70122