Current drug targets最新文献

{"title":"Decoding the Molecular Target Landscape of Chalcones: An Integrated Cheminformatics Analysis Using PubChem Patent Data, Protein Target Profiling, and Bioassay Activity Mapping.","authors":"Stalin Arulsamy, Kiruthiga Natarajan, Suresh Kumar Krishnan, Dinesh Babu","doi":"10.2174/0113894501502300261013021007","DOIUrl":"https://doi.org/10.2174/0113894501502300261013021007","url":null,"abstract":"<p><strong>Background: </strong>Chalcones are α,β-unsaturated ketone scaffolds with broad documented bioactivity. No prior study has simultaneously integrated structural validation, PAINS assessment, chemical-space clustering, human-target classification, bioassay hit-rate benchmarking, and patent analysis within a single computational framework.</p><p><strong>Methods: </strong>Seven hundred and twenty-two PubChem chalcone compounds were curated by SMARTS-based E-configured enone validation, ECFP4 k-means clustering, Bemis-Murcko decomposition, QED/Fsp³ profiling, and PAINS filtering. Protein target profiling (476 proteins; 145 human), bioassay benchmarking (12,981 assays; 81,667 data points; ChEMBL 34), and patent analysis (2,148 records) were integrated across PubChem exports.</p><p><strong>Results: </strong>Among 722 compounds, 686 (95.0 %) were E-configured; 50 (6.9 %) were PAINS-flagged; 195 Bemis-Murcko scaffolds (SDI = 0.270); mean QED = 0.444 ± 0.175; k = 2 clusters were statistically optimal. PAINS-flagged compounds showed significantly lower QED (0.392 vs. 0.449; p < 0.001). Among 145 human protein targets across 25 functional classes, key categories included tubulin isoforms (15), ABC transporters, MAO-A/B, and AChE. Bioassay analysis yielded 18,438 active hits (22.6 % overall); hit rates were: MAO 38.6 %, ABC transporters 32.2 %, AChE 31.8 %, and anticancer 31.5 %. China dominated patent filings (38.4 %); A61P35 (anticancer) was the leading IPC category.</p><p><strong>Discussion: </strong>Chalcones demonstrate robust polypharmacological engagement across multiple target classes. The low PAINS prevalence (6.9 %) confirms chemical tractability, while the inverse correlation between hit rate and assay dataset size underscores the need to account for reporting bias. The growing patent portfolio highlights the continued translational relevance of this scaffold.</p><p><strong>Conclusion: </strong>Chalcones represent a tractable, polypharmacological scaffold with target engagement validated across 145 human proteins. Hit-rate patterns provide reliable evidence even after accounting for reporting bias, although translational claims require independent experimental validation.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223534","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":"Discovery and Mechanistic Investigation of a Novel Kinase Inhibitor Targeting EGFR Resistance Mutations.","authors":"Lu Qi, Shuping Chen, Ying Zhang","doi":"10.2174/0113894501509463261008055141","DOIUrl":"https://doi.org/10.2174/0113894501509463261008055141","url":null,"abstract":"<p><strong>Background: </strong>The Epidermal Growth Factor Receptor (EGFR) serves as a core target in tumor-targeted therapy. Mutations in EGFR frequently lead to resistance against clinical Tyrosine Kinase Inhibitors (TKIs), underscoring the critical need to develop novel EGFR-targeting compounds for overcoming drug resistance.</p><p><strong>Methods: </strong>This study performed in silico virtual screening of candidate small-molecule compounds from databases based on the common pharmacophore features of seven clinically used EGFR-TKIs. The candidates were subjected to in silico physicochemical, pharmacochemical, and toxicity evaluations, as well as in silico prediction of kinase inhibitory activity, leading to the identification of ZINC44136419 as a computationally predicted candidate. Computational cross-validation of target proteins was conducted, and EGFR was identified as the putative core target protein through enrichment, interaction network, and mutation frequency analyses. Molecular docking of ZINC44136419 with wild-type and mutant EGFR was performed in silico, using gefitinib as a control to compare docking scores.</p><p><strong>Results: </strong>A computationally predicted kinase inhibitor candidate, ZINC44136419, was obtained. In silico analyses indicated that it exhibited the core pharmacophore features of EGFR-TKIs, was predicted to meet drug-likeness criteria, showed no predicted toxicity risks, was predicted to have high synthetic feasibility, and was identified as possessing a structurally distinct scaffold (low Tanimoto similarity to known inhibitors). In silico analyses revealed predicted selective inhibitory activity against the tyrosine kinase family, with target protein enrichment analysis showing significant association with protein kinase activity, suggesting EGFR as a putative core target protein with high mutation frequency. Notably, ZINC44136419 exhibited a more favorable docking score toward mutant EGFR than toward wild-type EGFR in silico, as compared to gefitinib.</p><p><strong>Discussion: </strong>This study relies entirely on computational simulations, which carry inherent methodological limitations. Nevertheless, the favorable druggability and favorable docking scores of this compound toward mutant targets in silico may provide candidate molecules and theoretical foundations for subsequent in vitro experimental validation, delivery system development, and the design of novel agents against EGFR drug resistance.</p><p><strong>Conclusion: </strong>As a computationally predicted EGFR-targeting compound, ZINC44136419 is predicted in silico to show preferential docking interactions with drug-resistant mutants through its structurally distinct scaffold, representing a preliminary candidate with potential translational value for overcoming EGFR-TKI resistance, pending experimental validation.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223460","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":"Topical Emulgel of Epigallocatechin Gallate and Olive Oil: A Quality-by-design Approach for Managing Chemotherapy-induced Alopecia.","authors":"Nishat Parveen Siddiqui, Nishi Agrawal, Ganesh Kumar, Sree Prakash Pandey, Shweta Yadav, Manoj Kumar, Ravi Shankar Pandey","doi":"10.2174/0113894501515184261009095214","DOIUrl":"https://doi.org/10.2174/0113894501515184261009095214","url":null,"abstract":"<p><strong>Introduction: </strong>Chemotherapy-Induced Alopecia (CIA) is a stressful effect associated with cancer therapy, mainly affecting hair follicles. Epigallocatechin Gallate (EGCG), a bioactive polyphenol, can be used for its antioxidant and hair growth-promoting effects. Hence, in this study, an EGCG- and olive oil-loaded emulgel was formulated to treat CIA.</p><p><strong>Method: </strong>EGCG-loaded emulgel was formulated using a factorial design with a QbD approach. Characterisation included rheological studies, transmission electron microscopy, particle size analysis, spreadability, and swelling index analysis. In vitro release and ex vivo studies were also performed. An in vivo study was conducted in rats, and the presence of EGCG in serum was detected by HPLC.</p><p><strong>Results: </strong>The optimised emulgel showed optimum rheological behaviour, and the particle size was 0.470 ± 0.14 μm with a zeta potential of -32.9 ± 2.3 mV. The in vitro release study showed maximum release of 59.44 ± 3.10% at the 7th hour. Ex vivo studies showed measurable skin deposition (212.08 ± 7.22μg/cm²) and limited transdermal permeation (23.50 ± 2.14% at 12 h). In vivo studies in a rat model demonstrated significant hair growth in the group treated with the optimised formulation. Furthermore, HPLC analysis of serum samples showed no detectable EGCG peak above the limit of detection of the method, suggesting minimal or no systemic absorption under the current analytical conditions.</p><p><strong>Discussion: </strong>The CIA adversely affects quality of life, and current treatments have limited efficacy. EGCG and olive oil show hair growth-promoting and antioxidant effects but suffer from poor dermal delivery and stability. Emulgel enhanced the stability and also provided significant sustained release. An in vivo study demonstrated that EGCG-olive oil-loaded emulgel can be a promising treatment strategy for CIA.</p><p><strong>Conclusion: </strong>Emulgel can be used to deliver EGCG, which addresses the limitations of formulations available and potentially can be adopted as a therapeutic approach in healthcare.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219919","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":"Computational Evaluation of Hydnocarpin as a Novel ROCK2 Inhibitor and Potential Regulator of Mitophagy in Cancer.","authors":"Aditi Kaushik, Chesta Shandilya, Geeta Swargiary, Saboor Khan, Pragya Singh, Shradheya R R Gupta, Indrakant K Singh, Shalini Mani","doi":"10.2174/0113894501525537261009064503","DOIUrl":"https://doi.org/10.2174/0113894501525537261009064503","url":null,"abstract":"<p><strong>Introduction: </strong>Impaired mitophagy in cancer cells leads to the accumulation of dysfunctional mitochondria, elevated ROS, and activation of pro-survival pathways, promoting tumour growth and metabolic adaptation. ROCK2, a serine/threonine kinase overexpressed in cancer, negatively regulates Parkin-mediated mitophagy, making it a rational therapeutic target.</p><p><strong>Methods: </strong>This study used an integrated in silico pipeline to identify phytocompounds from Indian medicinal plants predicted to inhibit ROCK2 and potentially modulate mitophagy. This study filtered a library of 31,496 natural product compounds from 325 medicinal plants (IMPPAT 2.0 database) using SwissADME based on Lipinski's, Veber's, Ghose's, and Pfizer's rules, yielding 598 drug-like compounds. Bioactivity scoring identified 49 NPCs with kinase inhibitory potential, which underwent Glide SP docking against ROCK2 (PDB: 7JNT), followed by ProTox-II toxicity profiling and XP docking.</p><p><strong>Results: </strong>Six compounds (Quercetin, Hydnocarpin, Annomontine, Camptothecin, 9- Methoxycamptothecin, and Methoxycamptothecin) showed binding affinities comparable to or exceeding reference inhibitors Fasudil and Y27632, with key interactions at conserved catalytic residues (Met172, Asp218, Asn219, Lys216). MD simulations showed that Hydnocarpin formed the most stable protein-ligand complex, with a consistent RMSD, persistent hydrogen bonding with Glu170, Met172, and Lys216, and minimal residue fluctuations, resembling Fasudil's dynamic profile. Quercetin, despite favourable docking scores, showed structural instability.</p><p><strong>Discussion: </strong>Integrated docking and MD analyses indicate Hydnocarpin exhibits superior binding stability compared to other screened phytocompounds, suggesting more favourable predicted binding under physiologically relevant simulation conditions.</p><p><strong>Conclusion: </strong>Hydnocarpin emerges as the most promising ROCK2 inhibitor among screened phytocompounds, supporting its potential as a mitophagy-modulating anticancer agent warranting further in vitro validation, as all findings reported here are computational predictions.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179928","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":"Computational Drug Repurposing Reveals Lopinavir and Ritonavir as Potential Inhibitors of APOL Proteins for Combating Kidney and Neuropsychiatric Disorders.","authors":"Muhammad Ali Raza, Muneer Ahmad, Cui Cheng, Muhammad Waleed Iqbal, Syed Zeeshan Haider, Muhammad Zohaib Nawaz, Xiaolin Shen","doi":"10.2174/0113894501494052261006091856","DOIUrl":"https://doi.org/10.2174/0113894501494052261006091856","url":null,"abstract":"<p><strong>Introduction: </strong>The Apolipoprotein L (APOL) family, particularly APOL1, APOL2, and APOL4, has been implicated in the pathogenesis of kidney injury, neuroinflammation, and several psychiatric disorders. However, there are currently no approved drugs available that can directly target these proteins, except for some APOL1-directed therapeutics. Identifying compounds that can modulate multiple APOL paralogs may therefore offer a promising therapeutic approach.</p><p><strong>Methods: </strong>In this study, a structure-based drug repurposing approach integrating molecular docking and MD simulations was employed to identify potential inhibitors of three APOL proteins. A library of 1,040 FDA-approved compounds was screened against APOL1, APOL2, and APOL4, followed by MD simulations to evaluate the stability and affinity of the identified complexes.</p><p><strong>Results: </strong>Docking analysis identified the antiviral drugs lopinavir and ritonavir as top-ranked potential inhibitors across all three APOL proteins. Ritonavir showed the strongest predicted binding affinity toward APOL1 (-10.46 kcal/mol) and APOL2 (-9.66 kcal/mol), while lopinavir exhibited the highest affinity for APOL4 (-9.21 kcal/mol). Subsequent MD simulations combined with RMSD, RMSF, RoG, hydrogen-bond, PCA, DCCM, and FEL analyses provided computational support for the persistence of the predicted protein-ligand interactions. MM/GBSA calculations further supported favorable predicted binding, with total energies ranging from -42.97 to -65.55 kcal/mol.</p><p><strong>Discussion: </strong>The identification of predicted shared inhibitors for APOL1, APOL2, and APOL4 is biologically significant due to their conserved structural features and overlapping pathological pathways. Repurposing clinically approved antivirals with established clinical use may provide a starting point for further investigation of APOL-targeting strategies.</p><p><strong>Conclusion: </strong>This study provides the first computational evidence supporting cross-paralog APOL inhibition by repurposed antiviral drugs. These findings provide a computational basis for the development of APOL-targeted therapeutic strategies and warrant further experimental validation.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179959","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":"HNF4-α Knockout Promotes HepG2 Cell Migration and Reduces Mitochondrial Membrane Potential under Hypoxic Conditions.","authors":"Tareq Saleh, Mohammad A Ismail, Mirvat Surakhy, Fairouz Nairat, Mohammad H Gharandouq, Dema Ali, Raghda Barham, Razan Aldiqs, Khairallah Al-Abdallat, Malek Zihlif, Nidaa A Ababneh","doi":"10.2174/0113894501512320261007111548","DOIUrl":"https://doi.org/10.2174/0113894501512320261007111548","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Hypoxia is a critical component of the tumor microenvironment contributing to metabolic reprogramming and drug resistance. Subsequently, elucidating the molecular mechanisms involved in hypoxia regulation in tumor cell models is essential.</p><p><strong>Methods: </strong>This study used CRISPR/Cas9 to knock out hepatocyte nuclear factor 4-alpha (HNF4-α) and hypoxia-inducible factor 1-alpha (HIF1-α) in HEPG2 cells. This study then assessed the effects of both knockouts (KO) on proliferation, migration, drug sensitivity, mitochondrial membrane stability, and gene expression in HEPG2 cells under both hypoxic and normoxic conditions.</p><p><strong>Results: </strong>Our data demonstrate that HIF1-α KO, but not HNF4-α KO, sensitizes HEPG2 cells to doxorubicin under hypoxic conditions. Additionally, the KO of both HIF1-α and HNF4-α enhances cell migration, irrespective of oxygen levels. Importantly, both HIF1-α and HNF4-α are required for cellular response to hypoxia and the maintenance of mitochondrial function, as evidenced by the loss of mitochondrial membrane potential increase under hypoxia in KO cells. Microarray-based transcriptomic profiling of HEPG2 cells revealed separation between HNF4-α and HIF1-α KO cells and controls under hypoxic versus normoxic conditions, with a markedly higher number of differentially expressed genes in hypoxia (up to 5,595 genes; adjusted p < 0.05, log2FC ±1.5). Both HNF4-α and HIF1-α contribute to hypoxia-responsive pathways, with impaired induction of key genes such as VEGFA and AK4 in KO cells, while GSEA indicated minimal effects of HNF4-α loss under hypoxia but pronounced metabolic pathway disruption in HIF1-α KO cells. Moreover, key regulators of mitochondrial function and mitophagy, including FUNDC1, MIEF1, and MIEF2, were upregulated in control hypoxic cells but not in KO cells.</p><p><strong>Discussion: </strong>These findings suggest that, in this single HEPG2 cell line model, HNF4-α contributes to the regulation of cell migration and mitochondrial stability under hypoxic conditions.</p><p><strong>Conclusion: </strong>Further investigation into the role of HNF4-α in tumor biology is encouraged.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179978","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":"Preface.","authors":"Hao Lin","doi":"10.2174/0113894501551272260924074714","DOIUrl":"https://doi.org/10.2174/0113894501551272260924074714","url":null,"abstract":"","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179972","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":"Sulfamethoxazole Attenuates Aluminum-induced Cognitive Impairment: In silico Evidence for BACE1 Interaction and In vivo Behavioral Assessment.","authors":"Aisha Altaf, Mehreen Arif, Wali Inam, Ghulam Abbas, Wajahat Mahmood","doi":"10.2174/0113894501509464261006043242","DOIUrl":"https://doi.org/10.2174/0113894501509464261006043242","url":null,"abstract":"<p><strong>Introduction/objective: </strong>BACE1 (Beta-Site Amyloid precursor protein-cleaving enzyme is a rate-limiting aspartic protease responsible for beginning Amyloid-β (Aβ) peptide synthesis, the major neurotoxic characteristic of Alzheimer's Disease (AD). Repurposing drugs with known safety profiles and Blood-Brain Barrier (BBB) permeability is a practical approach to treating AD. The current work combined in silico and in vivo approaches to investigate Sulfamethoxazole (SMZ) as a potential BACE1-interacting compound.</p><p><strong>Methods: </strong>Molecular docking of sulfamethoxazole to the BACE1 crystal structure (PDB: 1FKN) was done using AutoDock Vina. Female Sprague-Dawley rats (n = 6/group) received AlCl3 (500 mg/kg, i.g.) for 30 days to induce cognitive impairment, while SMZ (0.5, 1.0, and 1.5 mg/kg) was coadministered with AlCl3 for 30 days. On Days 31-36, locomotor activity assessments and the Morris Water Maze (MWM) were used to measure neurocognitive function.</p><p><strong>Results: </strong>Docking revealed prominent hydrogen-bond interactions between SMZ's sulfonamide oxygen atoms and the Tyr71, Asp228, and Thr72 residues, with the isoxazole ring occupying the hydrophilic S2 pocket of BACE1. Molecular docking analysis indicated a favorable interaction between SMZ and BACE1, suggesting BACE1 as a potential molecular target. In vivo, SMZ dosedependently reversed AlCl3-induced cognitive decline: reduced escape latency (F(1,27) = 117.0; p < 0.0001) and increased time spent in the platform quadrant (F(13.21; 6,6) = p < 0.05). Locomotor activity was unaffected (F(1.150; 3.24); p > 0.05), confirming the absence of CNS stimulation.</p><p><strong>Discussion: </strong>The findings provide preliminary computational and behavioral evidence supporting further investigation of SMZ in cognitive dysfunction. However, docking predictions do not establish direct BACE1 inhibition, and biochemical validation was not performed.</p><p><strong>Conclusion: </strong>SMZ attenuated AlCl3-induced cognitive impairment in rats and demonstrated a favorable predicted interaction with BACE1. Further studies are required to validate the proposed molecular mechanism and determine the therapeutic relevance of SMZ in cognitive dysfunction.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179931","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":"TYK2-Wnt5a Crosstalk in Psoriatic Arthritis: A Hypothesized Immunopharmacological Axis for Inflammation and Structural Remodelling.","authors":"Almeen Ansari, Japneet Purewal Singh, Gaurav Doshi","doi":"10.2174/0113894501519368261006050518","DOIUrl":"https://doi.org/10.2174/0113894501519368261006050518","url":null,"abstract":"<p><strong>Introduction: </strong>Psoriatic Arthritis (PsA) is a chronic immune-mediated inflammatory disease marked by synovitis, enthesitis, bone erosion, and pathological new bone formation, via the Interleukin-23/T helper cell-17 (IL-23/Th17) axis. Tyrosine Kinase 2 (TYK2) mediates downstream signaling of IL-23, IL-12, and type I Interferons (IFN-I), whereas Wnt5a regulates non-canonical Wnt signaling in inflammation and skeletal remodelling. This review proposes and examines TYK2- Wnt5a crosstalk in PsA as a testable mechanistic hypothesis rather than an established pathway.</p><p><strong>Methods: </strong>A narrative literature search was conducted using PubMed, Scopus, Web of Science, Google Scholar, and ClinicalTrials.gov, combining terms 'TYK2', 'Wnt5a', 'Psoriatic arthritis', and 'Wnt/β-catenin'. Relevant peer-reviewed articles, clinical studies, and webpages published up to 2026 were evaluated with no lower date limit. Evidence on TYK2 signaling, Wnt5a-mediated pathways, PsA immunopathogenesis, bone remodelling, and TYK2-targeted therapies was critically synthesized in narrative form.</p><p><strong>Results: </strong>TYK2 drives Th17/Th1-mediated inflammation via IL-17 and IL-22, while Wnt5a promotes osteoclastogenesis and aberrant bone remodelling. Emerging evidence suggests that the TYK2- driven cytokine network may influence Wnt5a expression, creating a pathogenic link between chronic inflammation and structural damage. This proposed axis currently rests on parallel, circumstantial evidence rather than direct experimental demonstration that TYK2-dependent signaling regulates Wnt5a expression in PsA tissue and is treated throughout as a hypothesis requiring direct validation.</p><p><strong>Discussion: </strong>Understanding the TYK2-Wnt5a interaction could explain the coexistence of erosive and proliferative bone changes in PsA and may reveal combination or pathway-directed therapeutic strategies.</p><p><strong>Conclusion: </strong>The TYK2-Wnt5a axis is a promising, hypothesis-generating target in PsA; further mechanistic and clinical studies are needed to validate it therapeutically.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179992","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":"In silico Prediction of Protein Targets for Benzofuranone Ring-containing Agents and Molecular Docking Analysis.","authors":"Fatma K Ata, Zerrin Çalışkan, Nehir Ö Özgentürk","doi":"10.2174/0113894501520248261002101424","DOIUrl":"https://doi.org/10.2174/0113894501520248261002101424","url":null,"abstract":"<p><strong>Background: </strong>Benzofuranone and its derivatives, which serve as drug precursors and intermediates due to their biological activity, are of great importance in the pharmaceutical industry. These heterocyclic molecules, composed of benzene and furan chains, possess antifungal, antiinflammatory, antidepressant, and anticancer properties. Given their pharmaceutical importance, mapping benzofuranone targets is a crucial step toward elucidating their molecular mechanisms of action and predicting potential side effects or cross-reactivity.</p><p><strong>Methods: </strong>In this study, we evaluated the in silico pharmacokinetic properties and potential protein targets of 15 derivatives of 2(3H)-Benzofuranone. Chemical structures were constructed and optimized using Spartan software. Next, SwissADME and ProTox servers were used to analyze pharmacokinetic features, while SwissTargetPrediction and STRING/Reactome were used to predict protein targets. In the final stage, the binding affinities of benzofuranone-hybrid molecules for Homo sapiens CDK1 and PLK1 proteins were calculated using molecular docking.</p><p><strong>Results: </strong>Ligands M and N were classified as class IV toxicity and met all Lipinski, Ghose, Veber, Egan, and Muegge filter conditions. The estimated LD50 values (rat acute oral toxicity) of these ligands were found to be 2000 mg/kg. Protein target prediction showed that the M ligand interacts with CDK1 and PLK1 proteins responsible for microtubule stability and spindle fiber organization. Molecular docking results predicted favorable binding of ligand M within the CDK1 and PLK1 binding sites, with mean binding energies of -8.2 kcal/mol and -7.7 kcal/mol, respectively.</p><p><strong>Discussion: </strong>These results were comparable to those obtained for the reference CDK1 inhibitor Abemaciclib (-10 kcal/mol) and the PLK1 inhibitor Volasertib (-8.2 kcal/mol). Furthermore, structural comparison with the reference inhibitor Abemaciclib predicted a partially overlapping binding pattern in the CDK1 binding domain (Lys33, Ile10, and Leu135) of ligand M.</p><p><strong>Conclusion: </strong>In our study, we identify ligand M as a promising starting scaffold for derivatizing benzofuranone- based compounds. In silico information provided in this study may serve as a basis for future researchers to design, synthesize, and evaluate new derivatives of this ligand with improved biological properties.</p>","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165607","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}