PLoS Genet. 2025 Jul 28;21(7):e1011793. doi: 10.1371/journal.pgen.1011793. Online ahead of print.

ABSTRACT

It is often difficult to ascertain whether patient-reported side-effects are caused by a drug, and if so, through which mechanism. Adverse side-effects are the primary cause of antipsychotic drug discontinuation rather than poor efficacy. Using a novel method combining genetic and drug binding affinity data, we investigated evidence of causal mechanisms for 80 reported side-effects of 6 commonly prescribed antipsychotic drugs which together target 68 receptors. We analysed publicly available drug binding affinity data and genetic association data using Mendelian randomization and genetic colocalization to devise a representative 'score' for each combination of drug, side-effect, and receptor. We show that 36 side-effects are likely caused by drug action through 30 receptors, which are mainly attributable to off-target effects (26 off-target receptors underlying 39 side-effects). This method allowed us to distinguish which reported side-effects have evidence of causality. Of individual drugs, clozapine has the largest cumulative side-effect profile (Score = 57.5, SE = 11.2), and the largest number of side-effects (n = 36). We show that two well-known side-effects for clozapine, neutropenia and weight change, are underpinned by the action of GABA and CHRM3 receptors respectively. Our novel genetic approach can map side-effects to drugs and elucidate underlying mechanisms, which could potentially inform clinical practice, drug repurposing, and pharmacological development. Further, this method can be generalized to infer the on-target and off-target effects of drugs at any stage of the drug development pipeline.

PMID:40720497 | DOI:10.1371/journal.pgen.1011793

J Cell Mol Med. 2025 Jul;29(14):e70736. doi: 10.1111/jcmm.70736.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate of < 10% and its incidences are continuously rising worldwide. This highlights an urgent need for effective therapies to reduce its burden. Repurposing commercially available non-cancer drugs that inhibit key drivers of PDAC may facilitate the rapid identification of effective drugs. In PDAC, the expression of the TBX2 and TBX3 transcription factors correlates with metastasis and poor patient survival. This study showed that when TBX3 was depleted in 2D and 3D PDAC cell culture models, the cells underwent senescence and had reduced proliferative ability and spheroid growth. Interestingly, TBX2 levels increased in shTBX3 cells and depleting TBX2 in these cells inhibited their migration. Our results thus demonstrated that TBX2 and TBX3 have distinct oncogenic functions and that any effective anti-PDAC drug must inhibit them both. The antifungal piroctone olamine, previously identified as a TBX2-/3-targeting drug in melanoma and rhabdomyosarcoma, inhibited the levels of TBX2 and TBX3 and recapitulated the phenotypes observed when they were knocked down in 2D and 3D PDAC cell culture models. Impressively, piroctone olamine was also effective in PDAC patient-derived organoids. Together, our data demonstrate the potential of piroctone olamine to be repurposed for treating TBX2-/3-dependent PDAC.

PMID:40717225 | DOI:10.1111/jcmm.70736

Adv Pharmacol. 2025;104:121-176. doi: 10.1016/bs.apha.2025.02.010. Epub 2025 Jun 23.

ABSTRACT

Repurposing conventional drugs as senotherapeutics offers a pragmatic and efficient approach to targeting cellular senescence, a key driver of aging-related diseases. Instead of relying solely on novel drug development, repurposing allows for the use of existing drugs with well-characterized pharmacokinetics, safety profiles, and clinical data, thereby accelerating their translation into senescence-targeted interventions. This chapter provides a comprehensive classification of senotherapeutics into senolytics, senomorphics, senoblockers, and senoreversers, detailing their mechanisms of action, molecular targets, and therapeutic applications. By categorizing these conventional agents based on their functional roles, this chapter presents a structured framework for understanding the pharmacological landscape of senotherapeutics. Additionally, this chapter discusses tissue-specific targeting, optimizing the dosing strategy to enhance the precision and safety of repurposed senotherapeutics. This chapter offers a systematic evaluation of drug repurposing, bridges the gap between preclinical and clinical applications, addressing both opportunities and challenges in repurposing the drugs. Eventually, this approach holds the potential to extend healthspan, mitigate age-related dysfunction, and provide more accessible and effective therapeutic options for disorders associated with cellular senescence.

PMID:40716928 | DOI:10.1016/bs.apha.2025.02.010

Eur J Pharmacol. 2025 Jul 25:177992. doi: 10.1016/j.ejphar.2025.177992. Online ahead of print.

ABSTRACT

BACKGROUND: the repurposing of non-steroidal anti-inflammatory drugs like ketoprofen (KET) has shown significant potential in melanoma treatment, with previously demonstrated anticancer properties. However, KET's low water solubility hinders its formulation at high concentrations.

OBJECTIVE: to overcome this challenge, KET-loaded oil-in-water nanoemulsions were developed and optimized, for the topical treatment of melanoma.

METHODS: formulations containing hydrophobic surfactants Capryol® 90, Lauroglycol™ 90, or Plurol® Diisostearique, hydrophilic surfactant Tween® 80, and cosurfactant/cosolvent Transcutol® were developed using spontaneous emulsification, and characterized in what concerned droplet size, polydispersity index (PDI), zeta potential, pH, stability, in vitro drug release, ex vivo drug permeation, and in vitro therapeutic efficacy and safety assessment.

KEY RESULTS: optimized formulations achieved a high drug loading, small (139.1 - 170.5 nm) and reasonably homogeneous (PDI 0.240 - 0.292) droplet sizes, neutral zeta potential (-6.38 to - 9.40 mV), and a skin compatible pH (around 4). Additionally, a controlled and high cumulative in vitro drug release was achieved for selected compositions, with biphasic characteristics (initial burst release followed by a more sustained release), as well as effective ex vivo skin permeation and retention, and good real-time stability. Optimized nanoemulsions significantly reduced B16.F10 murine melanoma cell viability in in vitro cytotoxicity assays, having an enhanced effect when compared to the free drug.

CONCLUSION: therefore, novel KET-loaded nanoemulsions were successfully developed, combining drug repurposing and a relevant scalability potential. Future research should explore these nanoplatforms' potential in in vivo models, investigating the possible synergy when combined with UVA radiation.

PMID:40716630 | DOI:10.1016/j.ejphar.2025.177992

Cardiology. 2025 Jul 26:1-23. doi: 10.1159/000547088. Online ahead of print.

ABSTRACT

INTRODUCTION: Coronary heart disease (CHD) and colorectal cancer (CRC) are common comorbidities among the elderly population. However, there is a lack of clinical prediction tools that utilize aging-related genes to forecast the onset and outcomes of these conditions in elderly patients.

METHODS: Gene expression data related to CHD and CRC were examined using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) of the National Center for Biotechnology Information (NCBI). The differentially expressed genes (DEGs) associated with aging, CHD, and CRC were identified. Predictive models for CHD diagnosis and prognostic risk prediction for CRC were constructed using the LASSO, Random Forest, and SVM-RFE techniques. Nomogram models have been developed to assess the prognosis of patients with CRC. Drug repositioning was performed to evaluate the shared predictive genes for diagnosing CHD and predicting CRC outcomes.

RESULTS: MYL9 and ULBP2 were identified as DEGs associated with aging, CHD, and CRC. Predictive models for CHD diagnosis and CRC risk prediction have been constructed. We developed a nomogram model to assess CRC prognosis and to identify MYL9 and ULBP2 as predictive genes. We assessed the potential of MYL9 and ULBP2 as therapeutic targets in elderly patients with CHD and CRC using a drug repositioning analysis.

CONCLUSION: We identified MYL9 and ULBP2 as aging-related markers for the diagnosis of CHD and the prognosis of CRC. In addition, we developed clinical tool models to facilitate the diagnosis of CHD and predict the prognosis of CRC, specifically in the elderly population.

PMID:40716429 | DOI:10.1159/000547088

J Transl Med. 2025 Jul 25;23(1):837. doi: 10.1186/s12967-025-06856-x.

ABSTRACT

Histone post-translational modifications (PTMs) have long been recognized as critical regulators of chromatin dynamics and gene expression, with aberrations in these processes driving tumorigenesis, immune escape, metastasis, and therapy resistance. While multi-omics technologies are generating ever more detailed maps of the histone landscape, translating these insights into clinical practice remains challenging. The ongoing convergence of high-throughput omics technologies and Artificial Intelligence (AI) is revolutionizing drug repositioning strategies, offering new precision tools to identify histone-targeted therapies for solid tumors. In this review, we explore how AI-driven multi-omics integration is currently reshaping therapeutic opportunities by uncovering novel drug-target-patient associations with unprecedented accuracy. Special focus is given to gynecologic and breast cancers, where chromatin remodeling dysregulation is particularly widespread, conventional therapeutic approaches have demonstrated substantial limitations and drug resistance represents a major clinical obstacle. These aggressive and lethal cancers exemplify areas where AI-powered repurposing of epi-drugs is making tangible clinical advances, enhancing tumor sensitivity to treatments like immunotherapy, but also offering new avenues to overcome challenging phenomena such as drug resistance and cancer relapse. We critically discuss these challenges and the effectiveness of a combination strategy approaches based on AI-driven patient stratification and biomarker-guided therapy optimization to maximize clinical benefits. In an era where precision oncology demands both specific drugs and the application of smarter strategies, the integration of AI, multi-omics, and targeting of chromatin remodelers may herald a transformative shift in the management of solid tumors, bridging the gap between biological insights and therapeutic innovation.

PMID:40713639 | DOI:10.1186/s12967-025-06856-x

Sci Rep. 2025 Jul 25;15(1):27086. doi: 10.1038/s41598-025-09417-w.

ABSTRACT

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, characterized by progressive motor and cognitive decline, leading to long-term disability and significantly impacting quality of life. While PD research has traditionally focused on dopaminergic neurons in the substantia nigra (SN), emerging evidence also suggests glial involvement in disease progression. So, this study explored PD-associated key genes from neuronal and glial cell types to uncover pathogenetic mechanisms and potential therapeutics by employing single-nucleus RNA sequencing (snRNA-seq) data from the accession number GSE184950. A total of 426,886 nuclei were analyzed, yielding 129,473 high-quality nuclei. Through rigorous quality control, clustering, and marker gene analysis using scVI and Scanpy, nine distinct cell types were delineated, including neurons, astrocytes, and microglia. 18 common differentially expressed genes (cDEGs) were identified across neuronal and glial cell types. Gene ontology (GO) and KEGG enrichment analyses revealed key terms associated with neurodegeneration, including PD. A total of six critical KGs, including HSPA1A, DNAJB1, BAG3, SYN1, CALB2, and NEFL, along with their key regulators, were identified by the protein-protein interaction network. Finally, three repurposed drugs (Celastrol, Withaferin-A, and Apomorphine) were suggested as the therapeutics agents for PD by molecular docking. In-silico ADME/T analyses were conducted using pkCSM and SwissADME to evaluate the pharmacokinetic properties of these compounds. These findings could shed light on PD mechanisms and hold promise for advancing diagnostics and therapies.

PMID:40715263 | DOI:10.1038/s41598-025-09417-w

Sci Rep. 2025 Jul 25;15(1):27103. doi: 10.1038/s41598-025-07303-z.

ABSTRACT

Drug-target interaction (DTI) prediction is a critical task in computational drug discovery, enabling drug repurposing, precise medicine, and large-scale virtual screening. Traditional in-silico methods, such as molecular docking, classical machine learning, and deep learning, have made significant progress in addressing this issue. However, existing approaches are hindered by computational inefficiencies, reliance on manual feature engineering, and struggles to generalize across diverse molecular structures, limiting their molecular capabilities. Recent advancements in Quantum Machine Learning (QML) are paving the way for its practical applications, unlocking unprecedented capabilities in predictive accuracy, scalability, and efficiency by leveraging the unique powers of quantum computing, namely superposition and entanglement. This study proposes QKDTI - Quantum Kernel Drug-Target Interaction, a novel quantum-enhanced framework for DTI prediction. It used Quantum Support Vector Regression (QSVR) with quantum feature mapping that takes into account a quantum feature space for molecular descriptors and allows encoding molecular and protein features, improved predictions of binding affinities. To enhance the model to be more computationally feasible, integration of the Nystrom approximation into the model allows providing an efficient kernel approximation while reducing overhead expenses. QKDTI was evaluated on benchmark datasets - Davis and KIBA, and validated independently on BindingDB. This model achieves 94.21% accuracy on DAVIS, 99.99% on KIBA, and 89.26% on BindingDB, significantly outperforming classical and other quantum models. Further, the statistical tests have been conducted on the compared models to provide the reliability of the results. This indicates that introducing quantum computing into DTI pipeline can revolutionize computational drug discovery by improving predictive accuracy and providing a better generalization over multiple datasets.

PMID:40715162 | DOI:10.1038/s41598-025-07303-z

Mol Cancer. 2025 Jul 25;24(1):206. doi: 10.1186/s12943-025-02396-6.

ABSTRACT

Cancer research is undergoing a paradigm shift from solely studying tumor cells to investigating systemic effects of cancer in the tumor macroevironment, with an emphasis on the interactions between host organs and tumors. The theory of homeostasis is an important basis for explaining biological functions from the perspective of the organism. Organic homeostasis relies on brain-body crosstalk through interception, immunoception, nociception and other supervisory processes, guaranteeing normal physiological function. Recent studies reveal that malignant tumors can hijack and exploit the brain and its central-peripheral neuronal networks to disrupt the body's homeostasis. Tumors likely disrupt normal brain-body crosstalk by establishing bidirectional brain-tumor connections. On the contrary, organism utilize these mechanisms to hinder tumorigenesis and progression. Standing at the perspective of brain-body crosstalk also promotes the conceptional evolution of cancer initiation and development, and more importantly, provides additional insight for cancer treatment. In this review, we summarize current knowledge about brain-body crosstalk under tumor-bearing contexts and propose some novel anti-cancer strategies.

PMID:40713672 | DOI:10.1186/s12943-025-02396-6

Assay Drug Dev Technol. 2025 Jul 21. doi: 10.1177/1540658X251361263. Online ahead of print.

ABSTRACT

Here, we briefly discuss 17 PCT patent applications related to drug repurposing that were published during the final quarter of 2024. As always, we have chosen the documents based on significance only, which gave us a wide range of applicants, active agents, and geographic representation. Applicants are not only from the United States and China but also from Japan, Germany, the United Kingdom, Canada, and even remote places such as Algeria and Iceland. Significantly, the contribution from Iceland is how to induce therapeutic hypothermia-but with entacapone, used in Parkinson's disease. The UK company, HealX, presents data showing that Angelman syndrome, an intractable neurodevelopmental disorder, could be treated with the common NSAID sulindac. Gliclazide, an old antidiabetic, could potentially treat schizophrenia, as inventors from Chinese Ping An-Shionogi report. These are only a few highlights from the stream of documents that have been issued towards the end of 2024.

PMID:40711937 | DOI:10.1177/1540658X251361263

Vet Sci. 2025 Jul 4;12(7):640. doi: 10.3390/vetsci12070640.

ABSTRACT

Canine otitis externa is a prevalent condition, and inadequate treatment may favor the emergence of multidrug-resistant microorganisms. Drug repurposing provides an alternative approach for the management of this disease. Thus, this study aimed at assessing the antimicrobial and antibiofilm properties of levamisole against bacterial strains recovered from dogs with otitis externa as well as its influence on biofilm growth dynamics during 120 h. A total of 50 clinical bacterial isolates were subjected to analysis. Planktonic bacterial susceptibility to levamisole was assessed by broth microdilution to determine the minimum inhibitory concentration (MIC), the lowest concentration that completely inhibits bacterial growth. The activity against mature biofilms was assessed by determining the minimum biofilm eradication concentration (MBEC). The effect of levamisole on biofilm formation was evaluated at the MIC and at two subinhibitory concentrations, with daily readings recorded at 48, 72, 96, and 120 h. MICs of levamisole ranged from 0.58 to 2.34 mg/mL. Levamisole reduced the biomass of mature biofilms (p < 0.05), with MBEC values ranging from 1.17 to 18.75 mg/mL, and biofilm formation was significantly reduced at the MIC concentration (1.17 mg/mL) for all isolates for 120 h (p < 0.05). Levamisole demonstrated potential as a preventive approach against biofilm-associated bacterial otitis.

PMID:40711300 | DOI:10.3390/vetsci12070640

Cells. 2025 Jul 20;14(14):1114. doi: 10.3390/cells14141114.

ABSTRACT

Calcium channel blockers (CCBs), originally developed for cardiovascular indications, have gained attention for their therapeutic potential in neuropsychiatric, endocrine, and pain-related disorders. In neuropsychiatry, nimodipine and isradipine, both L-type CCBs, show mood-stabilizing and neuroprotective effects, with possible benefits in depression, bipolar disorder, and schizophrenia. In endocrinology, verapamil, a non-dihydropyridine L-type blocker, has been associated with the preservation of pancreatic β-cell function and reduced insulin dependence in diabetes. CCBs may also aid in managing primary aldosteronism and pheochromocytoma, particularly in patients with calcium signaling mutations. In pain medicine, α2δ ligands and selective blockers of N-type and T-type channels demonstrate efficacy in neuropathic and inflammatory pain. However, their broader use is limited by challenges in central nervous system (CNS) penetration, off-target effects, and heterogeneous trial outcomes. Future research should focus on pharmacogenetic stratification, novel delivery platforms, and combination strategies to optimize repurposing of CCBs across disciplines.

PMID:40710367 | DOI:10.3390/cells14141114

Cells. 2025 Jul 15;14(14):1078. doi: 10.3390/cells14141078.

ABSTRACT

The mitochondrial regulator MNRR1 is reduced in several pathologies, including the mitochondrial heteroplasmic disease MELAS, and genetic restoration of its level normalizes the pathological phenotype. Here, we investigate the upstream mechanism that reduces MNRR1 levels. We have identified the hypoxic regulator HIF2α to bind the MNRR1 promoter and inhibit transcription by competing with RBPJκ. In MELAS cells, there is a pseudohypoxic state that transcriptionally induces HIF2α and stabilizes HIF2α protein. MELAS cybrids harboring the m.3243A > G mutation display reduced levels of prolyl hydroxylase 3 (PHD3), which contributes to the HIF2α stabilization. These results prompted a search for compounds that could increase MNRR1 levels pharmacologically. The screening of a 2400-compound library uncovered the antifungal drug nitazoxanide and its metabolite tizoxanide as enhancers of MNRR1 transcription. We show that treating MELAS cybrids with tizoxanide restores cellular respiration, enhances mitophagy, and, importantly, shifts heteroplasmy toward wild-type mtDNA. Furthermore, in fibroblasts from MELAS patients, the compound improves mitochondrial biogenesis, enhances autophagy, and protects from LPS-induced inflammation. Mechanistically, nitazoxanide reduces HIF2α levels by increasing PHD3. Chemical activation of MNRR1 is thus a potential strategy to improve mitochondrial deficits seen in MELAS. Finally, our data suggests a broader physiological pathway wherein two proteins, induced under severe (1% O2; HIF2α) and moderate (4% O2; MNRR1) hypoxic conditions, regulate each other inversely.

PMID:40710331 | DOI:10.3390/cells14141078

Chemistry. 2025 Jul 25:e04742. doi: 10.1002/chem.202404742. Online ahead of print.

ABSTRACT

Multiple sclerosis (MS), affecting over 2 million people globally, primarily causes neurological disability in individuals under 40. This autoimmune disorder involves the immune system attacking the myelin sheath in the central nervous system. Sphingosine-1-phosphate receptor 1 (S1PR1) is a promising therapeutic target, with approved drugs like ponesimod acting as S1PR1 agonists. However, the exact mechanism of ponesimod's action on S1PR1 and its therapeutic effects in MS remains unclear. Our study, combining metadynamics, single-cell transcriptomics, and drug repurposing, shows that ponesimod binds to S1PR1, causing the W2696.48 amino acid to flip downward. This flip weakens interactions within the phosphorylation-independent binding (PIF) motif while maintaining the N3077.49-F2656.44 interaction, activating Gi signaling. The downstream effects primarily involve the MAPK/ERK and PI3K-Akt pathways, which inhibit lymphocyte migration to lymph nodes, a crucial factor in ponesimod's clinical efficacy. Single-cell transcriptomic analysis further elucidates the regulatory network and pathways modulated by ponesimod in MS. Notably, due to potential hepatotoxicity, we identified valproic acid (VPA) as a potential adjunct therapy through drug repurposing. VPA reduces hepatotoxicity and demonstrates efficacy in treating MS in animal studies. This research provides valuable insights into ponesimod's mechanism in MS treatment and highlights the potential of drug repurposing to improve MS therapy.

PMID:40708468 | DOI:10.1002/chem.202404742

Sci Rep. 2025 Jul 24;15(1):26995. doi: 10.1038/s41598-025-12357-0.

ABSTRACT

Polydatin (PD), a stilbenoid resveratrol-derivative in Vitaceae, Liliaceae, and Leguminosae, exhibits pharmacological protection in metabolic disorders. This study investigated Polydatin, as a potential pan-PPAR agonist for treating non-alcoholic fatty liver disease (NAFLD). High-throughput-virtual-screening (HTVS) was performed to identify potential pan-PPAR agonists, followed by in vitro testing of Polydatin in HepG2 steatosis model. Effects on lipid metabolism and oxidative stress, PPAR signaling gene expression analysis, and GC-MS profiling were compared with the hepatoprotectant Silymarin. Pan-PPAR targeted HTVS of PhytoHub natural products database, followed by molecular docking/dynamics simulations, revealed lead-candidate, Polydatin, which was tested in steatotic cells for gene and protein deregulations by qRT-PCR and western blot, followed by GC-MS analysis of biochemical metabolites. HTVS revealed 53 potential pan-PPAR agonists. Molecular docking and dynamics simulations suggested that PD, a stable ligand for PPARs (α,β/δ,γ), exhibited strong binding. Polydatin treatment decreased ALT, triglycerides, and oxidative stress, wherein ROS and malondialdehyde levels decreased by 60.94% and 28%, respectively. PD upregulated PPARs, AMPK, GLUT2, and CPT1α, while downregulating lipogenic enzymes (ACC1, FASN, SCD1). GC-MS analysis revealed Polydatin mediated impact on saturated FFAs-palmitic acid, stearic acid, and unsaturated fatty acid product of SCD1, oleic acid. HTVS identified PD as a promising pan-PPAR agonist, which favorably ameliorated changes in lipid, glucose, and overall energy metabolism in steatotic NAFLD, by modulating PPAR(α,β/δ,γ) expressions and associated downstream lipogenic and lipid-utilization mechanisms, supporting anti-steatotic efficacy of Polydatin.

PMID:40707685 | DOI:10.1038/s41598-025-12357-0

Sci Rep. 2025 Jul 24;15(1):26948. doi: 10.1038/s41598-025-12645-9.

ABSTRACT

Breast cancer (BC) remains a leading cause of cancer-related mortality among women, with therapeutic resistance posing significant challenges. This study explores haloperidol (Halo), a clinically approved antipsychotic drug, for its potential antitumoral effects and ability to induce ferroptosis, a non-apoptotic programmed cell death linked to oxidative stress and lipid peroxidation. Halo's activity, partially mediated by sigma (σ) receptors, may enhance chemotherapy efficacy. This investigation delves into the role of heme oxygenase (HO), which was demonstrated to exhibit dual effects in ferroptosis as it's crucial for the modulation of iron intracellular levels and redox balance. Analysis of main related indicators depict a clear activation of ferroptotic cell death following Halo treatment evidenced by heightened oxidative stress conditions, as indicated by increased lipid peroxidation, elevated reactive oxygen species levels, significant glutathione depletion and mitochondrial membrane potential impairment. Further investigation revealed a protective role of HO-1 and the involvement of ferritinophagic process in MCF-7 BC cells. Additionally, it was evaluated whether Halo effect could be strictly dependent on its activity towards σ receptors and its efficacy in a 3D spheroid model. Data herein reported allow to elucidate Halo triggering of so-called non-canonical ferroptotic pathway suggesting its potential as a candidate for BC treatment.

PMID:40707640 | DOI:10.1038/s41598-025-12645-9

Int J Biol Macromol. 2025 Jul 22:146175. doi: 10.1016/j.ijbiomac.2025.146175. Online ahead of print.

ABSTRACT

Lung cancer (LC) remains one of the leading causes of cancer-related deaths globally, with both small and non-small cell lung cancer contributing to an estimated 1.80 million deaths annually. Drug resistance in LC treatment causes around 700,000 deaths globally and poses major economic challenges. While nearly 100 FDA-approved LC drugs exist, most target single proteins or pathways, making resistance more likely. There is an urgent need for multitargeted drugs that inhibit multiple pathways to reduce resistance and side effects. In this study, we examined 34 proteins from various LC-related pathways and prepared them for screening against the DrugBank library. Using high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) docking algorithms in Glide, we identified Imidurea (DB14075) as a promising multitargeted inhibitor. Docking scores ranged from -5.507 to -12.155 kcal/mol, and poses were refined through MM/GBSA calculations. Molecular fingerprinting was performed to analyse interaction patterns, and DFT and pharmacokinetics were assessed. Bonding angles were optimised to evaluate relative binding energy, followed by 100 ns MD simulations in water to assess stability and effectiveness. Imidurea showed strong multitargeted inhibitory effects across all 34 LC proteins, with docking scores between -5.507 and - 12.155 kcal/mol. MD simulations further supported its stability in binding to these targets. In MTT assays on A549 cells, Imidurea demonstrated dose-dependent anticancer effects, causing significant cell cycle arrest and cell death at 100 μg/mL. Imidurea is an affordable compound with promising multitargeted anticancer potential, particularly beneficial for developing nations and underprivileged groups. While these computational and in vitro MTT assays are encouraging, further detailed in vitro and in vivo studies are necessary to validate their efficacy and safety before clinical application.

PMID:40706931 | DOI:10.1016/j.ijbiomac.2025.146175

Lancet Neurol. 2025 Jul 21:S1474-4422(25)00226-1. doi: 10.1016/S1474-4422(25)00226-1. Online ahead of print.

ABSTRACT

Primary cilia are ubiquitous organelles, which play essential roles in sensing and transducing cellular signals and in mediating key developmental pathways. Pathogenic variants in genes encoding for ciliary proteins give rise to a spectrum of disorders termed primary ciliopathies. The archetypal neurodevelopmental ciliopathy is Joubert syndrome. However, in the past decade, primary cilia have been implicated in several other neurological disorders, including neurodevelopmental disorders, malformations of cortical development, neurodegenerative disorders, and psychiatric disorders. Therapeutic approaches for cilia-related disorders are still scarce. Strategies based on gene therapy and antisense oligonucleotides show promising results, especially for the treatment of retinal ciliopathies, and are currently moving towards clinical translation. Other approaches based on drug repurposing or the use of small molecules, despite positive results in a variety of cellular and animal models, are still in the experimental stage.

PMID:40706604 | DOI:10.1016/S1474-4422(25)00226-1

Mol Pharmacol. 2025 Jul 5;107(8):100059. doi: 10.1016/j.molpha.2025.100059. Online ahead of print.

ABSTRACT

The cycle of GTP binding and hydrolysis controls heterotrimeric G proteins, and mutations reducing GTPase activity result in constitutive G protein signaling. In Gαq (gene: GNAQ) such mutations cause uveal melanoma and Sturge-Weber syndrome. Finding pharmacological agents that inhibit Gαq will be beneficial for research with therapeutic potential. Previously discovered bacterial depsipeptides (FR900359 and YM-254890) bind directly to Gαq and stabilize its inactive complex with GDP, but suffer from limitations of distribution and bioavailability. We used the established Gαq-YM-254890 complex structure to dock small-molecule drugs into the depsipeptide binding site of Gαq. Our in silico screen of 5000 Food Drug and Administration-approved, experimental, and withdrawn drugs predicted that thiazolidinediones are potential ligands of Gαq. Analysis of G protein coupled receptor-stimulated G protein GTPγS binding demonstrated that troglitazone (441 Da) inhibited Gq nucleotide exchange with the IC50 of ∼31.7 μM. The thiazolidinedione analogs, rosiglitazone and pioglitazone, had no effect. High concentrations of troglitazone modestly inhibited Gi1 and Gs, but not G13. In G protein thermal stability assays, troglitazone and FR900359 stabilized purified Gαq-GDP, indicating direct binding. Consistent with its negative effect on Gq signaling, in MIN6 mouse insulinoma cells, troglitazone inhibited Ca2+ mobilization, extracellular regulated protein kinase phosphorylation, and insulin secretion stimulated by the Gq-coupled M3 muscarinic cholinergic receptor. Troglitazone and FR900359 inhibited proliferation of MEL92.1 uveal melanoma cells driven by a GNAQ-Q209L driver mutation, but not of SK-MEL-28 cells driven by BRAF-V600E. Together, our study shows that troglitazone may be a promising new lead for the development of a <500 Da small-molecule therapeutic Gαq inhibitor. SIGNIFICANCE STATEMENT: Troglitazone, unlike other thiazolidinediones, directly binds and inhibits activity of heterotrimeric G protein Gq, with a weaker effect on Gi. Troglitazone may find usage as a repurposed drug scaffold to build novel small-molecule Gαq inhibitors with better bioavailability than depsipeptide Gαq inhibitors.

PMID:40706404 | DOI:10.1016/j.molpha.2025.100059

Biol Reprod. 2025 Jul 24:ioaf164. doi: 10.1093/biolre/ioaf164. Online ahead of print.

ABSTRACT

Endometriosis is a chronic neuroinflammatory disorder believed to impact on wellbeing of more than 190 million women and people assigned female at birth. The defining hallmark of endometriosis is the growth of endometrial-like tissue as "lesions" outside the uterus. Most lesions are found in the pelvis and referred to as peritoneal (superficial), ovarian (endometrioma) or deep depending on location. Patients often suffer from persistent pelvic pain which can be worse during menstruation as well as fatigue, gastro-intestinal and urinary symptoms and mood disorders that impact on quality of life. It is estimated 30-50% of patients with endometriosis may have problems conceiving. Diagnostic delay is ~7-9 years after first symptoms. There are currently no reliable biomarker(s). Advances in imaging have improved diagnosis of ovarian and deep subtypes but definitive diagnosis may require invasive laparoscopic surgery. Standard treatment options include surgery as well as drugs that suppress ovarian hormones which have unwanted side effects. New approaches to symptom management have been informed by the reframing of endometriosis as a multisystem disease. Genetic studies have identified shared risk factors with inflammatory and other chronic pain conditions. Alterations in hormonal, metabolic and inflammatory pathways in samples from endometriosis patients have opened-up new avenues for medical therapy, including drug repurposing. There is increased interest in non-medical and self-management strategies including nutrition. In this narrative review we discus recent research studies and ongoing clinical trials which are addressing the need for novel approaches to reduce the impact of symptoms on quality of life.

PMID:40704733 | DOI:10.1093/biolre/ioaf164