J Chem Inf Model. 2025 Apr 25. doi: 10.1021/acs.jcim.5c00070. Online ahead of print.

ABSTRACT

The extraction of biomedical data has significant academic and practical value in contemporary biomedical sciences. In recent years, drug repositioning, a cost-effective strategy for drug development by discovering new indications for approved drugs, has gained increasing attention. However, many existing drug repositioning methods focus on mining information from adjacent nodes in biomedical networks without considering the potential inter-relationships between the feature spaces of drugs and diseases. This can lead to inaccurate encoding, resulting in biased mined drug-disease association information. To address this limitation, we propose a new model called Dual-Feature Drug Repurposing Neural Network (DFDRNN). DFDRNN allows the mining of two features (similarity and association) from the drug-disease biomedical networks to encode drugs and diseases. A self-attention mechanism is utilized to extract neighbor feature information. It incorporates two dual-feature extraction modules: the single-domain dual-feature extraction (SDDFE) module for extracting features within a single domain (drugs or diseases) and the cross-domain dual-feature extraction (CDDFE) module for extracting features across domains. By utilizing these modules, we ensure more appropriate encoding of drugs and diseases. A cross-dual-domain decoder is also designed to predict drug-disease associations in both domains. Our proposed DFDRNN model outperforms six state-of-the-art methods on four benchmark data sets, achieving an average AUROC of 0.946 and an average AUPR of 0.597. Case studies on three diseases show that the proposed DFDRNN model can be applied in real-world scenarios, demonstrating its significant potential in drug repositioning.

PMID:40278791 | DOI:10.1021/acs.jcim.5c00070

Metabolites. 2025 Apr 9;15(4):255. doi: 10.3390/metabo15040255.

ABSTRACT

BACKGROUND/OBJECTIVES: Drug development for complex diseases such as NAFLD is often lengthy and expensive. Drug repurposing, the process of finding new therapeutic uses for existing drugs, presents a promising alternative to traditional approaches. This study aims to identify potential repurposed drugs for NAFLD by leveraging disease-disease relationships and drug-target data from the BioSNAP database.

METHODS: A bipartite network was constructed between drugs and their target genes, followed by the application of the BiClusO bi-clustering algorithm to identify high-density clusters. Clusters with significant associations with NAFLD risk genes were considered to predict potential drug candidates. Another set of candidates was determined based on disease similarity.

RESULTS: A novel ranking methodology was developed to evaluate and prioritize these candidates, supported by a comprehensive literature review of their effectiveness in NAFLD treatment.

CONCLUSIONS: This research demonstrates the potential of drug repurposing to accelerate the development of therapies for NAFLD, offering valuable insights into novel treatment strategies for complex diseases.

PMID:40278384 | DOI:10.3390/metabo15040255

Cells. 2025 Apr 11;14(8):575. doi: 10.3390/cells14080575.

ABSTRACT

Lithium is prescribed as a mood stabilizer for bipolar disorder and severe depression. However, the mechanism of action of lithium is unknown and there are major side effects associated with prolonged medication. This motivates a search for safer alternative drug repurposing candidates. Given that the drug mechanism may be encoded in transcriptional changes, we generated the gene expression profile for acute lithium treatment of cortical neuronal cultures. We found that the lithium-associated transcription response harbors a significant component that is the reverse of that seen in human brain samples from patients with major depression, bipolar disorder, and a mouse model of depression. Interrogating publicly available drug-driven expression data, we found that cardiotonic steroids drive gene expression in a correlated manner to our acute lithium profile. An analysis of the psychiatric medication cohort of the Norwegian Prescription Database showed that cardiotonic prescription is associated with a lower incidence of lithium prescription. Our transcriptional and epidemiological observations point towards cardiotonic steroids as possible repurposing candidates for lithium. These observations motivate a controlled trial to establish a causal connection and genuine therapeutic benefit in the context of depression.

PMID:40277900 | DOI:10.3390/cells14080575

Cells. 2025 Apr 8;14(8):559. doi: 10.3390/cells14080559.

ABSTRACT

Rare diseases typically evade the application of the standard drug discovery and development pipelines due to their understudied molecular etiology and the small market size. Herein, we report a rare disease-directed workflow that rapidly studies the molecular features of the disorder, establishes a high-throughput screening (HTS) platform, and conducts an HTS of thousands of approved drugs to identify and validate repositioning drug candidates. This study examines the pediatric neurological disorder caused by de novo mutations in YWHAG, the gene encoding the scaffolding protein 14-3-3γ, and the workflow discovers nuclear relocalization and a severe drop in 14-3-3γ binding to its phosphorylated protein partners as the key molecular features of the pathogenic hotspot YWHAG mutations. We further established a robust in vitro HTS platform and screened ca. 3000 approved drugs to identify the repositioning drug candidates that restore the deficient 14-3-3γ-phosphotarget interactions. Our workflow can be applied to other 14-3-3-related disorders and upscaled for many other rare diseases.

PMID:40277885 | DOI:10.3390/cells14080559

J Helminthol. 2025 Apr 25;99:e55. doi: 10.1017/S0022149X25000276.

ABSTRACT

Benzimidazoles are the most frequently prescribed therapeutic options for treating trichinellosis in clinical settings; however, they have a lot of disadvantages. Therefore, researchers are focusing on the hunt for substitute chemicals. The goal of the current study was to compare the effectiveness of albendazole and the anti-diabetic medication metformin loaded on chitosan nanoparticles in treating mice infected with various stages of T. spiralis infection. 160 mice were included in the present study and divided into 8 groups: 6 experimentally treated groups, and positive and negative control groups. For studying the intestinal and parenteral phase, each group was broken into two more subgroups (a and b) according to the time of drug administration. The effects of albendazole, albendazole-loaded NPs, metformin, metformin-loaded NPs, combined albendazole and metformin, and metformin and albendazole-loaded NPs were assessed using parasitological studies, histopathological examination, and ultrastructural examination using SEM.Statistically significant differences were detected in all studied subgroups compared to the control infected subgroup both in the intestinal and muscular phases. The greatest decrease in recovered adult worm and muscle larvae numbers was achieved by ABZ & MET/ Cs NPs. These findings were confirmed by histopathological examination. SEM examination of the tegument of T. spirals adult worms and muscle larvae showed destruction with multiple degenerative changes.Our results suggested that metformin and its combination with albendazole especially when loaded on chitosan nanoparticles could be potential therapeutic alternative drugs against trichinellosis.

PMID:40275564 | DOI:10.1017/S0022149X25000276

Orphanet J Rare Dis. 2025 Apr 24;20(1):195. doi: 10.1186/s13023-025-03711-6.

ABSTRACT

BACKGROUND: Chanarin-Dorfman syndrome (CDS) is a multisystemic autosomal recessive rare disorder. CDS is caused by variants in the abhydrolase domain containing 5 (ABHD5) encoding gene (CGI-58), which ultimately leads to excessive lipid storage, and therefore a high abundance of cellular lipid droplets (LDs). Although the molecular etiology of the disease was described many years ago, no treatment for CDS is currently available.

RESULTS: To further characterize the molecular basis of the disease and to uncover new treatment avenues, we used skin fibroblasts originating from a young patient diagnosed with CDS due to a homozygous nonsense mutation. We show that dysfunctional ABHD5 does not only affect LDs, but also influences other metabolic-related organelles; the mitochondria and peroxisomes. Additionally, we found that expressing functional ABHD5 in CDS patient cells reduced LD number. Finally, we developed and applied a high content-based drug repurposing screen based on a collection of ∼2500 FDA approved compounds, yielding several compounds that affected LD total area and size.

CONCLUSIONS: Our findings enhance the understanding of the dysfunction underlying CDS and propose new avenues for the treatment of CDS patients.

PMID:40275410 | DOI:10.1186/s13023-025-03711-6

Sci Rep. 2025 Apr 24;15(1):14315. doi: 10.1038/s41598-025-98689-3.

ABSTRACT

Congenital factor (F) VII deficiency is caused by mutations in the F7 gene. The p.Q160R variant manifests with bleeding episodes due to reduced FVII activity and antigen in patient plasma, most likely caused by protein misfolding and intracellular retention. As current replacement therapy is expensive and requires frequent intravenous injections, there is an unmet need for new and less invasive therapeutic strategies. Drug repurposing allows for rapid, more cost-effective discovery and implementation of new treatments, and identification of pharmacological enhancers of FVII variant activity would be of clinical importance. High-throughput screening of > 1800 FDA-approved drugs identified the orally available histone deacetylase inhibitor abexinostat and the inhaled surfactant tyloxapol as enhancers of FVII p.Q160R variant activity. The positive hits were verified in an in vitro cell model transiently expressing wild type or variant FVII and ex vivo in patients' plasma. Both drugs showed a dose-response effect on FVII antigen and activity levels in conditioned cell medium and on FVII activity in patients' plasma. In conclusion, the efficacy of the FDA-approved drugs abexinostat and tyloxapol in enhancing FVII variant activity constitute a proof of principle for high-throughput identification of drugs that may be feasible for novel treatment of FVII deficiency.

PMID:40274887 | DOI:10.1038/s41598-025-98689-3

Bioorg Chem. 2025 Apr 10;160:108464. doi: 10.1016/j.bioorg.2025.108464. Online ahead of print.

ABSTRACT

Pancreatic cancer has a poor prognosis with limited therapeutic options, necessitating novel treatment strategies. While B3GALT5 enzyme overexpression has been reported in pancreatic cancer cases, effective mechanisms to suppress its activity remain unexplored. In this study, we utilized bioinformatics and in silico studies to evaluate the relationship between B3GALT5 enzyme and pancreatic cancer. Through molecular docking analysis, FDA-approved drugs 6-AZA-UTP and itraconazole were identified as potential B3GALT5 enzyme inhibitors. Biological evaluation on MIA PaCa-2 and AsPC-1 pancreatic cancer cell lines demonstrated that both compounds significantly reduced cell viability. Flow cytometry analysis revealed that both drugs effectively suppressed B3GALT5 enzyme activation by decreasing SSEA-3 expression. Furthermore, both compounds exhibited potent anti-tumor effects by inhibiting cell adhesion, colony formation, and migration while inducing apoptosis in pancreatic cancer cells. Notably, both drugs demonstrated favorable ADMET profiles with no carcinogenic or toxic effects. Our investigations revealed that 6-AZA-UTP and itraconazole can effectively suppress B3GALT5 enzyme activity, resulting in tumor suppression and metastasis inhibition. These findings suggest that either 6-AZA-UTP or itraconazole can inhibit B3GALT5 enzyme activity and may serve as promising therapeutic options for pancreatic cancer treatment through drug repurposing strategy.

PMID:40273705 | DOI:10.1016/j.bioorg.2025.108464

Front Med (Lausanne). 2025 Apr 9;12:1576375. doi: 10.3389/fmed.2025.1576375. eCollection 2025.

ABSTRACT

Myocardial Infarction (MI) and lung cancers are major contributors to mortality worldwide. While seemingly diverse, the two share common risk factors, such as smoking and hypertension. There is a pressing need to identify bidirectional molecular signatures that link MI and lung cancer, in order to improve clinical outcomes for patients. In this study, we identified common differentially expressed genes between MI and lung cancer. Specifically, we identified 1,496 upregulated and 1,482 downregulated genes in the MI datasets. By focusing on the 1,000 most upregulated and downregulated genes in Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Carcinoma (LUSC), we identified 35 genes that are common across MI, LUAD, and LUSC. Functional enrichment analysis revealed shared biological processes, such as "inflammatory response" and "cell differentiation." The Cox proportional hazards model demonstrated a significant association between the shared genes and overall survival in lung cancer patients, as well as with smoking history in these patients. In addition, a machine learning model based on the expression of the shared genes distinguished MI patients from controls, achieving an AUROC of 0.72 and an AUPRC of 0.86. Finally, based on drug repurposing analysis, we proposed FDA-approved drugs potentially targeting the upregulated genes as novel therapeutic options for the co-occurring conditions of MI and lung cancer. Overall, our findings highlight the similarities in molecular makeup between lung cancer and MI.

PMID:40270498 | PMC:PMC12014433 | DOI:10.3389/fmed.2025.1576375

Front Pharmacol. 2025 Apr 8;16:1539032. doi: 10.3389/fphar.2025.1539032. eCollection 2025.

ABSTRACT

Background: Parkinson's disease (PD), a prevalent and progressive neurodegenerative disorder, currently lacks effective and satisfactory pharmacological treatments. Computational drug repurposing represents a promising and efficient strategy for drug discovery, aiming to identify new therapeutic indications for existing pharmaceuticals. Methods: We employed a drug-target network approach to computationally repurpose FDA-approved drugs from databases such as DrugBank. A literature review was conducted to select candidates not previously reported as pharmacoprotective against PD. Subsequent in vitro evaluation utilized Cell Counting Kit-8 (CCK8) assays to assess the neuroprotective effects of the selected compounds in the SH-SY5Y cell model of Parkinson's disease induced by 1-methyl-4-phenylpyridinium (MPP+). Furthermore, an in vivo mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was developed to investigate the mechanisms of action and therapeutic potential of the identified drug candidates. Results: Our approach identified 176 drug candidates, with 28 selected for their potential anti-Parkinsonian effects and lack of prior PD-related reporting. CCK8 assays showed significant neuroprotection in SH-SY5Y cells for Omaveloxolone and Cyproheptadine. In the MPTP-induced mouse model, Cyproheptadine inhibited interleukin-6 (IL-6) expression and prevented Tyrosine Hydroxylase (TH) downregulation via the MAPK/NFκB pathway, while Omaveloxolone alleviated TH downregulation, potentially through the Kelch-like ECH-associated protein 1 (KEAP1)-NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. Both drugs preserved dopaminergic neurons and improved neurological deficits in the PD model. Conclusion: This study elucidates potential drug candidates for the treatment of Parkinson's disease through the application of computational repurposing, thereby underscoring its efficacy as a drug discovery strategy.

PMID:40264664 | PMC:PMC12011821 | DOI:10.3389/fphar.2025.1539032

Curr Drug Res Rev. 2025 Apr 21. doi: 10.2174/0125899775365699250408091801. Online ahead of print.

ABSTRACT

Computational drug repositioning has emerged as an efficient approach to discovering new indications for existing drugs, offering lower risk and cost compared to traditional drug discovery methods. Various computational approaches have been developed, including targetbased, gene-expression-based, phenome-based, and multi-omics-based methods. Recent advancements leverage diverse data sources, such as biomedical databases and online healthrelated information. Techniques incorporating drug structure and target information have shown promising results in predicting new drug indications. Despite significant progress, challenges remain, including data noise reduction, method ensemble, negative sample selection, and data sparseness. Overall, computational drug repositioning continues to be a valuable tool in drug discovery and development.

PMID:40264316 | DOI:10.2174/0125899775365699250408091801

Sci Rep. 2025 Apr 22;15(1):13975. doi: 10.1038/s41598-025-88388-4.

ABSTRACT

The 3C-like protease (3CLpro) is essential in the SARS-CoV-2 life cycle and a promising target for antiviral drug discovery, as no similar proteases exist in humans. This study aimed to identify effective SARS-CoV-2 inhibitors among FDA-approved drugs. Previous computational analysis revealed several drugs with high binding affinity to the 3CLpro active site. In vitro enzymatic assays confirmed that ten of these drugs effectively inhibited the enzyme. To evaluate their impact on viral replication, we used non-infectious SARS-CoV-2 sub-genomic replicons in lung and intestinal cells. Amcinonide, eltrombopag, lumacaftor, candesartan, and nelfinavir inhibited replication at low micromolar concentrations. Lumacaftor showed IC50 values of 964 nM in Caco-2 cells and 458 nM in Calu-3 cells, while candesartan had IC50 values of 714 nM and 1.05 µM, respectively. Furthermore, dual combination experiments revealed that amcinonide, pimozide, lumacaftor, and eltrombopag acted as potent inhibitors at nanomolar concentrations when combined with candesartan. This study highlights lumacaftor, candesartan, and nelfinavir as effective inhibitors of SARS-CoV-2 replication in vitro and emphasizes their potential for repurposing as antiviral treatments. These findings support future clinical trials and may lead to breakthroughs in COVID-19 treatment strategies.

PMID:40263343 | DOI:10.1038/s41598-025-88388-4

Mol Biol Rep. 2025 Apr 22;52(1):410. doi: 10.1007/s11033-025-10524-0.

ABSTRACT

Drug repurposing is the process of using currently approved drugs for a novel treatment or medical condition for which it was not previously indicated. Despite promising preclinical and clinical results, most of the newly designed senotherapeutic agents synthesized have limited clinical utility due to individual and organ-specific variations in aging phenotype and adverse side effects. All these limitations indicate that further clinical research is required to determine the effectiveness of repurposed senotherapeutic drug interventions, such as metformin, for age-related diseases. Metformin exerts diverse senotherapeutic effects on various aging tissues at different metabolic conditions. Although not exhibiting senolytic properties, metformin has effectively suppressed cellular senescence and senescence-associated secretory phenotype (SASP) in age-related diseases (ARDs). Targeting specific SASP-related signaling pathways with metformin may offer new therapeutic benefits to alleviate the detrimental effects of senescent cells accumulated in most common ARDs in the elderly. Metformin was also the first drug evaluated for its senescence-targeting effects in a large clinical trial named "Targeting Aging with Metformin (TAME)". In this review, we critically evaluate the literature to highlight senotherapeutic mechanisms in which metformin can be therapeutically repurposed for the prevention and treatment of ARDs.

PMID:40261556 | DOI:10.1007/s11033-025-10524-0

Int J Antimicrob Agents. 2025 Apr 19:107522. doi: 10.1016/j.ijantimicag.2025.107522. Online ahead of print.

ABSTRACT

RNA-binding proteins (RBPs) are essential regulators of cellular RNA processes, including RNA stability, translation, and post-translational regulation. During viral infections, RBPs are key regulators of the viral cycle due to their interaction with both host and viral RNAs. Herein we initially explore the roles of specific RBP families, namely heterogeneous nuclear ribonucleoproteins (hnRNPs), DEAD-box helicases, human antigen R (HuR), and the eukaryotic initiation factors of the eIF4F complex, in viral RNA replication, translation, and assembly. Next, we examine the potential of these RBPs as host-targeting antivirals against pandemic-prone RNA viruses that have been gaining momentum in recent years. Targeting RBPs could disrupt cellular homeostasis, leading to unintended effects on host cells; however, RBPs have been successfully targeted mainly in anticancer therapies, showcasing that their modulation can be safely achieved by drug repurposing. By disrupting key viral-RBP interactions or modulating RBP functions, such therapeutic interventions aim to inhibit viral propagation and restore normal host processes. Thus, conceivable benefits of targeting RBPs as alternative antiviral strategies include their broad-spectrum activity and potential for combination therapies with conventional antivirals, reduced or delayed resistance development, and concomitant enhancement of host immune responses. Our discussion also highlights the broader implications of leveraging host-directed therapies in an attempt to overcome viral resistance. Finally, we emphasize the need for continued innovation to refine these strategies for broad-spectrum antiviral applications.

PMID:40258479 | DOI:10.1016/j.ijantimicag.2025.107522

In Silico Pharmacol. 2025 Apr 17;13(2):67. doi: 10.1007/s40203-025-00347-z. eCollection 2025.

ABSTRACT

Morphine and heroin dependence are growing concerns worldwide. Drug dependence is one of the greatest challenges, and developing alternative therapeutic strategies is essential. Due to few treatment options in pain management, morphine, a potent analgesic, is widely prescribed, but it carries a high risk of abuse. For the management of drug dependence, we have limited treatment options available, therefore, strategies should be developed to manage drug-seeking behaviors in clinical settings. We tried to find any FDA-approved drug targeting µ-opioid receptors through the in-silico approach. We screened around 186 FDA-approved drugs; we observed several drugs showing better docking scores with good affinity. We found vilazodone, indinavir, and lorazepam as potential drugs based on their affinity and mechanism of action. Later, these drugs were screened against human µ-opioid (PDB ID:8EF6) and other novel drug targets (5HT1 and TLR-4) that are associated with morphine dependence. Following docking, density functional theory (DFT), molecular dynamics (MD), molecular mechanics, and general born surface area (MM-GBSA) were performed to calculate the stability and ligand-protein binding free energies. Vilazodone, indinavir and lorazepam showed promising docking, MD, the energy gap between the HOMO and LUMO chemical reactivity, and MM-GBSA results compared to morphine and naloxone. We propose that these three drugs have huge potential to reverse the morphine and heroin dependence in diseased subjects near future.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00347-z.

PMID:40255259 | PMC:PMC12006581 | DOI:10.1007/s40203-025-00347-z

Microb Pathog. 2025 Apr 17:107586. doi: 10.1016/j.micpath.2025.107586. Online ahead of print.

ABSTRACT

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb) and is a growing public health problem worldwide. Within the innate immune response, we highlight the secretion of the antimicrobial peptide LL-37, which is crucial for Mtb elimination in infected cells. Previous reports have shown that CEBPα activation induces LL-37 independently of its main inducer, vitamin D, under endoplasmic reticulum (ER) stress. In this study, we report that infection with Mtb causes ER stress in pulmonary epithelial cells and macrophages. The stress induces the activation of CEBPα, which in turn promotes the LL-37 expression. Furthermore, the participation of CEBPα is necessary for the correct clearance of Mtb in an in vitro infection model. We identify candidate drugs (mycophenolic acid, indapamide, and glibenclamide) capable of activating CEBPα and promoting LL-37 through in silico assays. The effect of the drugs was corroborated by gene and protein expression analysis. Finally, we observed that treatment with these drugs improves bacterial clearance in infected cells. Our results lead us to suggest CEBPα as a potential therapeutic target as an adjuvant in the standard treatment of tuberculosis, seeking a reduction in treatment time, and thus a lower appearance of drug resistance.

PMID:40252936 | DOI:10.1016/j.micpath.2025.107586

Comput Biol Chem. 2025 Apr 15;118:108471. doi: 10.1016/j.compbiolchem.2025.108471. Online ahead of print.

ABSTRACT

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the overexpression of poly-ADP ribose polymerase 1 (PARP1), a key enzyme in DNA repair. Targeting PARP1 with inhibitors presents a promising therapeutic strategy, particularly given the limited treatment options for TNBC. This study employed in silico methodologies to evaluate the pharmacokinetic and inhibitory potential of FDA-approved drugs and compounds derived from Onosma. dichroantha root extracts against PARP1. Virtual screening and molecular docking identified Midazolam, Olaparib, Beta-sitosterol, and 1-Hexyl-4-nitrobenzene as top candidates, exhibiting strong binding affinities of -10.6 kcal/mol, -9.9 kcal/mol, -6.83 kcal/mol, and -5.53 kcal/mol respectively. Molecular dynamics simulations (MDS) over 100 nanoseconds revealed that Beta-sitosterol formed the most stable complex with PARP1, demonstrating minimal structural deviations and robust hydrogen bonding. The Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) analysis further confirmed Beta-Sitosterol and Olaparib superior binding free energy (ΔGbind= -175.43 kcal/mol and -180.8 kcal/mol respectively), highlighting its potential as a potent PARP1 inhibitor. ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling indicated that Beta-Sitosterol adheres to Lipinski's Rule of Five, with high intestinal absorption (95.88 %) and blood-brain barrier permeability (0.824), despite low water solubility. Protein-protein interaction analysis identified key PARP1-associated proteins, including CASP3, CASP7, and XRCC1, suggesting broader therapeutic implications. These findings underscore the potential of Beta-Sitosterol as a novel PARP1 inhibitor for TNBC treatment, combining computational validation with favorable pharmacokinetic properties. The study also highlights the utility of drug repurposing and plant-derived compounds in developing targeted therapies for TNBC, paving the way for further preclinical and clinical investigations.

PMID:40252254 | DOI:10.1016/j.compbiolchem.2025.108471

Sci Rep. 2025 Apr 18;15(1):13445. doi: 10.1038/s41598-025-98629-1.

ABSTRACT

Traditional drug design faces significant challenges due to inherent chemical and biological complexities, often resulting in high failure rates in clinical trials. Deep learning advancements, particularly generative models, offer potential solutions to these challenges. One promising algorithm is DrugGPT, a transformer-based model, that generates small molecules for input protein sequences. Although promising, it generates both chemically valid and invalid structures and does not incorporate the features of approved drugs, resulting in time-consuming and inefficient drug discovery. To address these issues, we introduce DrugGen, an enhanced model based on the DrugGPT structure. DrugGen is fine-tuned on approved drug-target interactions and optimized with proximal policy optimization. By giving reward feedback from protein-ligand binding affinity prediction using pre-trained transformers (PLAPT) and a customized invalid structure assessor, DrugGen significantly improves performance. Evaluation across multiple targets demonstrated that DrugGen achieves 100% valid structure generation compared to 95.5% with DrugGPT and produced molecules with higher predicted binding affinities (7.22 [6.30-8.07]) compared to DrugGPT (5.81 [4.97-6.63]) while maintaining diversity and novelty. Docking simulations further validate its ability to generate molecules targeting binding sites effectively. For example, in the case of fatty acid-binding protein 5 (FABP5), DrugGen generated molecules with superior docking scores (FABP5/11, -9.537 and FABP5/5, -8.399) compared to the reference molecule (Palmitic acid, -6.177). Beyond lead compound generation, DrugGen also shows potential for drug repositioning and creating novel pharmacophores for existing targets. By producing high-quality small molecules, DrugGen provides a high-performance medium for advancing pharmaceutical research and drug discovery.

PMID:40251288 | DOI:10.1038/s41598-025-98629-1

Int J Biol Macromol. 2025 Apr 16:143217. doi: 10.1016/j.ijbiomac.2025.143217. Online ahead of print.

ABSTRACT

Flaviviridae family comprises some of the most vulnerable viruses known for causing widespread outbreaks, high mortality rates, and severe long-term health complications in humans. Viruses like Dengue (DENV), Zika (ZIKV) and Hepatitis C (HCV) are endemic across the globe, especially in tropical and subtropical regions, infecting multiple tissues and leading to significant health crises. Investigating virus-host interactions across tissues can reveal tissue-specific drug targets and aid antiviral drug repurposing. In this study, we employed a multi-step computational approach to construct a comprehensive virus-human interactome by integrating virus-host protein-protein interactions (PPIs) with tissue-specific gene expression profiles to study key protein targets associated with Flaviviridae infections. Mapping drug-target predictions revealed druggable proteins - CCNA2 in peripheral blood mononuclear cells (PBMC) and EIF2S2, CDK7 and CARS in the liver, with Tamoxifen, Sirolimus, Entrectinib and L-cysteine as potential repurposable drugs, respectively. Further protein-ligand docking and molecular dynamics (MD) simulations were conducted to assess the stability of the complexes. These findings highlight common druggable human targets exploited by DENV, ZIKV and HCV, providing a foundation for broad-spectrum antiviral therapies. By focusing on shared host pathways and targets in viral replication, we propose promising drug candidates, supporting the development of unified therapeutic strategies against Flaviviridae viruses.

PMID:40250655 | DOI:10.1016/j.ijbiomac.2025.143217

RSC Adv. 2025 Apr 17;15(16):12331-12341. doi: 10.1039/d5ra01341k. eCollection 2025 Apr 16.

ABSTRACT

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare and aggressive tumor of the primary central nervous system primarily affecting children. It typically originates in the cerebellum and brain stem and is associated with a low survival rate. While standard chemotherapy has been used as a primary treatment for AT/RTs, its success rate is unsatisfactory, and patients often experience severe side effects. Therefore, there is an urgent need to develop new and effective treatment strategies. One promising approach for identifying new therapies is drug repurposing. Although many FDA-approved drugs have been repurposed for various cancers, there have been no reports of such applications for AT/RTs. In this study, a library of 2130 FDA-approved drugs was screened using a high-throughput screening system against 2D traditional cultures and 3D spheroid cultures of AT/RT cell lines (BT-12 and BT-16). From this screening, colchicine, a non-chemotherapeutic agent, was identified as a promising candidate. It exhibited IC50 values of 0.016 and 0.056 μM against 2D BT-12 and 2D BT-16 cells, respectively, and IC50 values of 0.004 and 0.023 μM against 3D BT-12 and BT-16 spheroid cultures. Additionally, the cytotoxic effects of colchicine on human brain endothelial cells and human astrocytes were evaluated, and CC50 > 20 μM was observed, which is over two orders of magnitude higher than its effective concentrations in AT/RT cells, indicating considerably lower toxicity to normal brain cells and brain endothelial cells. In conclusion, colchicine shows significant potential to be repurposed as a treatment for AT/RTs, providing a safer and more effective therapeutic option for this rare and challenging disease.

PMID:40248220 | PMC:PMC12004362 | DOI:10.1039/d5ra01341k