Current drug targets最新文献

{"title":"Rational Design and Evaluation of Novel ATR Inhibitors for Osteosarcoma Therapy: An Integrated 3D-QSAR, Molecular Docking, and Molecular Dynamics Study.","authors":"Panchen Zhao, Zheng Lian, Xuexiao Ma, Hao Tao","doi":"10.2174/0113894501491611261001070851","DOIUrl":"https://doi.org/10.2174/0113894501491611261001070851","url":null,"abstract":"<p><strong>Background: </strong>Ataxia Telangiectasia and Rad3-related protein kinase (ATR) is a central regulator of the DNA damage response and represents an attractive therapeutic target in tumors with high replication stress, including osteosarcoma. This study aimed to characterize the structure- activity relationships of a distinct ATR-targeting scaffold and to guide the rational design of new inhibitors using integrated computational approaches.</p><p><strong>Methods: </strong>A dataset of 23 previously reported derivatives was used to construct a Comparative Molecular Similarity Indices Analysis (CoMSIA) 3D-QSAR model, with 18 compounds assigned to the training set and five to an external test set. Steric, electrostatic, hydrophobic, hydrogen-bond donor, and hydrogen-bond acceptor fields were evaluated. Model performance was assessed by leave-oneout cross-validation, Y-randomization, bootstrap resampling, external validation, Golbraikh-Tropsha criteria, rm 2-based metrics, and applicability-domain analysis. CoMSIA contour maps were then used to guide analogue design. Molecular docking was independently performed against both the engineered ATR-pocket surrogate 5UK8 and the recently resolved native human ATR structure 9L40 to assess the robustness of the predicted binding mode across distinct receptor models. The resulting 5UK8-19h-5 and 9L40-19h-5 complexes were subsequently subjected to molecular dynamics simulations to evaluate the dynamic stability and persistence of the predicted ligand-protein interactions.</p><p><strong>Results: </strong>The optimal CoMSIA model showed good statistical performance, with a cross-validated q² of 0.521 and a non-cross-validated r² of 0.996. External validation yielded an R² of 0.691 and a concordance correlation coefficient of 0.831, while randomization and bootstrap analyses further supported model stability. Electrostatic and hydrophobic interactions were the major contributors to activity, followed by hydrogen-bonding effects. Guided by the resulting structure-activity patterns, five new analogues were designed, of which 19h-5 showed the highest predicted activity (pIC₅₀ = 8.521). Cross-structure docking revealed a broadly conserved binding mode of 19h-5 in the 5UK8 and 9L40 binding pockets, and subsequent molecular dynamics simulations supported the stability of both predicted complexes.</p><p><strong>Discussion: </strong>The findings indicate that ATR inhibitory activity within this scaffold is governed by coordinated electrostatic, hydrophobic, and hydrogen-bonding features. Compared with previously studied aminopyrazine- and morpholinopyrimidine-based ATR inhibitors, the present scaffold provides a distinct structural framework and expands the chemical space available for ATR-targeted drug design. The concordance between the surrogate and native ATR models, together with the dynamic stability observed in molecular dynamics simulations, reduces the structural uncertainty associated with relying so","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Human Nectin-4 and Signaling Lymphocyte Activation Molecule/SLAM as Potential Receptors for the Spike Protein of SARS-CoV-2 and its Variants.","authors":"Subhajit Dasgupta","doi":"10.2174/0113894501482948260928072953","DOIUrl":"https://doi.org/10.2174/0113894501482948260928072953","url":null,"abstract":"<p><strong>Introduction: </strong>SARS-COV2 Spike protein is critical for virus entry as well as proinflammatory responses in host cells. The Spike epitopes form heteromeric complexes with HLA-DR alleles and Toll-like Receptors 2, 4, and 8. The Receptor Binding Domain of the Spike protein binds with Angiotensin Converting Enzyme2 (ACE2) as the first known host receptor. In this context, the aim is to identify a host cell surface protein as a potential receptor for the SARS-CoV-2 family that not only allows viral entry but also triggers inflammation.</p><p><strong>Methods: </strong>Virus Spike Receptor Binding Domain (RBD) sequences, human Nectin4 and Signaling Lymphocyte Activation Molecule (SLAM) (amino acid sequences and corresponding Protein Database: PDB) were used for the in silico experiments cell free digital experiments. The Dimer Packing Quality (FSCOR) for heterodimeric protein/peptide structure formation was determined by using Preddimer software. The construction of PDB files for peptide sequences was performed by Avogadro's software. Schrodinger PyMol software was used for the Molecular Docking and Molecular Dynamics experiments to determine interactions between two unrelated protein/peptide molecules and to generate heterodimeric structures.</p><p><strong>Results: </strong>The experiments showed the ability of SARS-CoV-2 Spike RBD (constructed PDB: SpRD 2, 5, 7, and 8) to bind human Nectin4 and SLAM, generating heterodimeric structures at pH 7.2 (p < 0.05). Molecular Docking and Molecular Dynamics demonstrated sequence-specific binding patterns between virus RBD fragments (RMSD: 0.05- 1.1 Angstrom) and human Nectin4 (RMSD 32.375 Angstroms) and SLAM (RMSD 27.451 Angstroms) proteins.</p><p><strong>Discussion: </strong>SARS-CoV-2 Spike forms heterodimeric structures with Nectin4 and SLAM.</p><p><strong>Conclusion: </strong>Computational modeling identifies Nectin4 and SLAM as potential receptors for the virus Spike protein.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Models to Molecules: Integrative Strategies in Herbal Product-based Drug Discover.","authors":"Vibha Rani","doi":"10.2174/0113894501545651260929110824","DOIUrl":"https://doi.org/10.2174/0113894501545651260929110824","url":null,"abstract":"","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stimuli-responsive Graphene Nanoplatforms Co-delivering Self-amplifying RNA, circRNA, and cGAMP for Cancer Immunotherapy: A Narrative Review.","authors":"Iram Jahan, Jiyaul Hak, Mohd Salman, Neha Joshi, Huma Khan, Ankur Grag","doi":"10.2174/0113894501483997260924092514","DOIUrl":"https://doi.org/10.2174/0113894501483997260924092514","url":null,"abstract":"<p><strong>Introduction: </strong>Cancer immunotherapy has emerged as a transformative therapeutic strategy; however, its efficacy remains limited by tumor heterogeneity, immune suppression, and inefficient delivery of nucleic acid therapeutics. Graphene-based nanomaterials have attracted considerable attention as multifunctional carriers because of their high surface area, tunable surface chemistry, and stimuli-responsive properties.</p><p><strong>Methods: </strong>This narrative review critically summarizes recent advances in stimuli-responsive graphene nanoplatforms for the co-delivery of self-amplifying RNA (saRNA), circular RNA (circRNA), and cGAMP. A conceptual multifunctional graphene-based delivery framework is proposed to guide future experimental research in cancer immunotherapy. Particular emphasis is placed on graphene functionalization strategies, RNA conjugation approaches, tumor-responsive release mechanisms, and synergistic immune activation pathways.</p><p><strong>Results: </strong>Graphene nanoplatforms demonstrate significant potential to protect nucleic acid therapeutics from degradation while enabling controlled release in response to pH, redox, enzymatic, and near-infrared stimuli. The integration of saRNA, circRNA, and cGAMP provides complementary therapeutic benefits, including prolonged antigen expression, enhanced molecular stability, and potent activation of the STING pathway. This combination promotes coordinated activation of innate and adaptive immunity, resulting in improved dendritic cell maturation, T-cell priming, and antitumor immune responses.</p><p><strong>Discussion: </strong>The multifunctional nature of graphene-based nanocarriers offers opportunities for simultaneous delivery of multiple immunotherapeutic agents while reducing systemic toxicity. Nevertheless, challenges related to biosafety, biodegradability, large-scale manufacturing, and regulatory approval remain barriers to clinical translation.</p><p><strong>Conclusion: </strong>Stimuli-responsive graphene nanoplatforms co-delivering saRNA, circRNA, and cGAMP represent a promising next-generation strategy for precision cancer immunotherapy. Continued advances in graphene engineering and translational nanomedicine may facilitate their future clinical application.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plant-derived Bioactive Compounds in Schizophrenia: Pharmacological Mechanisms and Emerging Drug Targets.","authors":"Marta Raquel Costa Loureiro, João Paulo Fernandes, António Paranhos","doi":"10.2174/0113894501514494260916073129","DOIUrl":"https://doi.org/10.2174/0113894501514494260916073129","url":null,"abstract":"<p><strong>Introduction: </strong>Schizophrenia is a chronic and heterogeneous psychiatric disorder characterized by positive and negative symptoms, together with cognitive dysfunction. Because current antipsychotic-based treatment remains limited for negative and cognitive symptoms, adjunctive strategies targeting additional pathophysiological pathways are needed.</p><p><strong>Methods: </strong>This narrative review synthesized preclinical and clinical evidence on selected medicinal plants, standardized extracts and plant-derived bioactive compounds investigated as adjunctive approaches in schizophrenia. Evidence was organized according to plant source or compound, putative mechanisms of action, preclinical findings, clinical evidence, symptom domains, antipsychoticassociated adverse effects and pharmacological pathways.</p><p><strong>Results: </strong>The reviewed interventions targeted oxidative stress, neuroinflammation, glutamatergic and dopaminergic dysfunction, endocannabinoid modulation, mitochondrial function and neurotrophic signaling. Randomized clinical evidence was available for a limited subset of candidates, including cannabidiol, Withania somnifera, L-theanine, curcumin-based formulations, Ginkgo biloba and Panax quinquefolius. Most other agents remained supported mainly by preclinical, mechanistic or indirect clinical evidence. Potential benefits included improvement in positive, negative or cognitive symptom domains and attenuation of selected antipsychotic-associated adverse effects.</p><p><strong>Discussion: </strong>The evidence base remains heterogeneous, with substantial variation in formulations, doses, treatment duration, outcome measures and translational maturity. Bioavailability and standardization are major challenges for several compounds, particularly polyphenols.</p><p><strong>Conclusion: </strong>Plant-based interventions should be positioned as adjunctive, not alternative, approaches. Further adequately powered clinical trials using standardized preparations are required to clarify efficacy, safety, optimal dosing and clinical relevance in schizophrenia.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computationally Assisted Natural Product Discovery: Unraveling the Potential of Natural Products in Anticancer Drug Development.","authors":"Neha Atale, Vibha Rani","doi":"10.2174/0113894501480294260904045119","DOIUrl":"https://doi.org/10.2174/0113894501480294260904045119","url":null,"abstract":"<p><p>Despite substantial progress in immunotherapies and targeted therapies, alongside conventional modalities such as surgery, radiotherapy, and chemotherapy, cancer treatment continues to pose significant challenges. Natural products are central to advancing innovative anticancer agents in oncological research, enabling the scientific community to explore novel compounds derived from nature for combating malignancies. Notably, several agents like vincristine and quercetin have been demonstrated to have substantial efficacy in managing leukemia and breast cancer, etc. Computational approaches represent a foundational strategy in drug discovery among diverse methodologies. This review reveals the role of natural products as prospective anticancer agents and delineates structure- based drug discovery methods and their contributions to rationalizing therapeutic development. This also highlights the deployment of natural products in cancer therapeutics, prevailing computational strategies leveraging these compounds for drug design, and their critical role in the discovery continuum. Ultimately, natural products combined with established computational drug discovery frameworks offer considerable potential in the management of cancer treatment.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Potential Therapeutic Target Genes for Bipolar Disorder through Systematic Druggable Genome-wide Mendelian Randomization.","authors":"Yan-Ting Jin, Tian-Yu Zhang, Chang-Cheng Xiang, Cai-Yi Ma, Cheng-Bing Huang","doi":"10.2174/0113894501495610260907110248","DOIUrl":"https://doi.org/10.2174/0113894501495610260907110248","url":null,"abstract":"<p><strong>Introduction: </strong>Bipolar Disorder (BD) is a severe psychiatric condition with high heritability and clinical heterogeneity. Despite numerous genetic variants linked to BD through Genome- Wide Association Studies (GWAS), the molecular mechanisms and effective therapeutic targets remain unclear. This study aims to identify potential therapeutic targets for BD using a systematic approach.</p><p><strong>Methods: </strong>In this study, we performed a systematic druggable genome-wide Mendelian Randomization (MR) analysis to identify potential therapeutic target genes for BD. We integrated large-scale GWAS data, expression Quantitative Trait Loci (eQTL) datasets, and druggable gene resources to construct a set of 6,888 potential druggable genes. MR methods were applied to infer causal relationships between these genes and BD. Additionally, Protein-Protein Interaction (PPI) network analysis, Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to explore the biological functions and pathways involved. Drug enrichment analysis was performed to assess the association between identified genes and approved psychiatric drugs, while Bayesian colocalization analysis was used to provide evidence for causal genetic signals underlying potential druggable targets.</p><p><strong>Results: </strong>Our MR analysis revealed 34 genes with significant causal associations with BD. These genes were found to be predominantly involved in immune regulation, neuro-metabolic processes, and oxidative stress-related pathways. Drug enrichment analysis identified a close association between these genes and several approved psychiatric drugs, including trifluoperazine, clozapine, and alprazolam. Further, Bayesian colocalization analysis provided strong evidence for GSTM1 and CD52 as potential druggable targets for BD, suggesting that their gene expression shares causal genetic signals with disease susceptibility.</p><p><strong>Discussion: </strong>Our findings support previous studies linking immune dysregulation to BD, with the identified genes enriched in immune-metabolic and oxidative stress pathways. A key limitation is the reliance on GWAS data primarily from European cohorts, which may limit the generalizability to other populations.</p><p><strong>Conclusion: </strong>This study prioritizes candidate druggable genes for BD through integrative analysis of GWAS, eQTL, MR, drug enrichment, and colocalization evidence. Our findings provide insights into BD-related molecular mechanisms and suggest potential avenues for target prioritization and drug repurposing research.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural Product-derived Binders of Protein Arginine Deiminase 4 (PAD4) Predicted Using Molecular Modeling.","authors":"Bryan German Pineda-Cagua, Sofia Ruiz-Hernández, Fátima de Lourdes Ochoa-González, Julio E Castañeda-Delgado, Alfredo Juarez-Saldivar, Gildardo Rivera, Edgar E Lara-Ramírez","doi":"10.2174/0113894501488854260831064519","DOIUrl":"https://doi.org/10.2174/0113894501488854260831064519","url":null,"abstract":"<p><strong>Background: </strong>Natural products serve as vital scaffolds for novel drug discovery. PAD4 is an attractive target dysregulated in chronic diseases like Alzheimer's, cancer, and rheumatoid arthritis. Given the lack of clinically approved synthetic inhibitors, exploring structurally diverse natural products offers a promising strategy for novel drug development.</p><p><strong>Methods: </strong>Molecular modeling using ligand-based virtual screening, consensus molecular docking using four scoring functions available on the Smina and Vina software, ADME-Tox consensus filtering, and molecular dynamics analysis with GROMACS were applied to virtually screen natural products from the COCONUT database as potential PAD4 binders.</p><p><strong>Results: </strong>The docking validation parameters (redocking RMSD < 2 Å, AUC-ROC > 70 %) confirmed the effective discrimination of known PAD4 inhibitors from decoys. From the COCONUT database, 29,164 compounds were initially filtered by similarity to noncovalent PAD4 inhibitors. Among these, 10 compounds were selected as the top candidate inhibitors using a multi-faceted virtual screening protocol that combined a novel consensus pharmacological score with binding affinity, druglikeness, and ADMET evaluations. PASS predictions further corroborated their PAD4 inhibitory potential. Molecular dynamics of the top five compounds confirmed active-site stability and noncovalent interactions with catalytic residues Asp350, Arg374, His471, Asp473, and Cys645. Structurally, these candidates represent diverse natural chemical classes, including benzenoids, alkaloids, and amino acid derivatives.</p><p><strong>Discussion: </strong>The multifaceted virtual screening conducted in this work resulted in confident prioritization of five potential PAD4 inhibitors. Further in vitro and in vivo studies are needed to confirm their functional inhibitory activity in diseases in which this target is dysregulated.</p><p><strong>Conclusion: </strong>Five natural chemistry-binders of PAD4 were identified by detailed molecular modeling studies. They could be used as chemical scaffolds for future medicinal chemistry drug design.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective Role of Aconitum heterophyllum Ethanolic Root Extract Against Streptozotocin-induced Diabetes in Rats.","authors":"Gaurav Kumar, Jayendra Kumar","doi":"10.2174/0113894501517590260915073125","DOIUrl":"https://doi.org/10.2174/0113894501517590260915073125","url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to evaluate the antidiabetic potential of Aconitum heterophyllum ethanolic extract (AHEE) in streptozotocin-induced diabetic Wistar rats. Diabetes mellitus, a metabolic disorder marked by hyperglycemia, oxidative stress, hyperlipidemia, and reduced insulin production, leads to elevated glucose, cholesterol, triglycerides, and LDL levels, with decreased HDL and body weight. Despite its global prevalence, diabetes is largely managed rather than cured. Owing to their bioactive compounds, medicinal plants like A. heterophyllum, known for antioxidant and anti-inflammatory properties, may protect pancreatic β-cells by reducing oxidative stress and inflammation.</p><p><strong>Methods: </strong>After extract preparation and preliminary testing, 30 adult Wistar rats were used for invivo screening. Using Glibenclamide (GLBMD 5 mg/kg) as the standard drug and Streptozotocin (STZ, 55 mg/kg) as the diabetes-inducing agent, the animals were divided into five groups (n=6) and treated for 21 days. The impact of AHEE was evaluated by measuring biochemical parameters and histological alterations.</p><p><strong>Results: </strong>STZ-induced diabetic rats exhibited significantly elevated blood glucose levels (p < 0.05) and reduced body weight compared with controls. Treatment with AHEE (100 and 200 mg/kg) for 21 days significantly lowered fasting blood glucose and improved body weight from the first week onward. Both doses also ameliorated dyslipidemia, improved liver (SGPT, SGOT, ALP, TB) and kidney (urea, creatinine) function markers, and restored normal histoarchitecture of the liver, kidney, and pancreatic tissues.</p><p><strong>Discussion: </strong>The antihyperglycemic effect of AHEE, along with improvements in biochemical and histopathological parameters, suggests its potential to protect pancreatic β-cells and alleviate diabetes- associated metabolic and organ dysfunction. These findings indicate that AHEE possesses significant antidiabetic, hepatoprotective, and renoprotective activities in STZ-induced diabetic rats.</p><p><strong>Conclusion: </strong>This study found that when AHEE was administered to STZ-induced diabetic rats, both dosages exhibited antidiabetic and hypolipidemic effects.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nucleic Acid Foundation Models for siRNA Drug Design.","authors":"Liping Ren, Hasan Zulfiqar, Zheng Shi, Guangya Xu, Yang Zhang, Nanchao Luo","doi":"10.2174/0113894501516654260904091333","DOIUrl":"https://doi.org/10.2174/0113894501516654260904091333","url":null,"abstract":"<p><strong>Background: </strong>Small interfering RNA (siRNA) therapeutics have become an important class of nucleic acid medicines. Meanwhile, nucleic acid foundation models and RNA language models have demonstrated promising performance in selected RNA-related tasks and may support siRNA drug design through transferable sequence representation learning.</p><p><strong>Approach: </strong>This mini-review selectively surveys and critically evaluates representative nucleic acid foundation models and their potential roles in siRNA design, including representation learning, lowdata adaptation, multitask prediction, generative design, and multi-objective optimization. Particular attention is given to RNA language models such as RNA-FM and RiNALMo, while DNA, regulatory, unified DNA-RNA, and multimodal models are positioned according to their direct or contextual relevance to siRNA development.</p><p><strong>Results: </strong>Current models can be broadly grouped into DNA genomic language models, RNA language models, epigenomic/regulatory models, unified DNA-RNA models, and multimodal biomolecular foundation models. Across these categories, existing models provide complementary capabilities for sequence, structure, regulatory context, and cross-modal representation, but none yet constitutes a complete framework for therapeutic siRNA design.</p><p><strong>Discussion: </strong>Although these models show strong transferability across genomic and RNA tasks, their value for siRNA-specific therapeutic design remains insufficiently established. A central challenge is the mismatch between the natural RNA grammar and the therapeutic oligonucleotide grammar. Real siRNA development requires simultaneous consideration of efficacy, specificity, chemical modification, stability, immunogenicity, off-target effects, delivery compatibility, and manufacturability.</p><p><strong>Conclusion: </strong>Future progress will depend on modification-aware representations, therapeutic oligonucleotide datasets, multimodal integration, interpretable and experimentally testable outputs, robust cross-dataset and cross-protocol evaluation, and Pareto-based multi-objective selection. These requirements define a practical roadmap for moving from transferable RNA representations to therapeutically credible siRNA design systems.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}