Current Drug Targets

BACKGROUND: The cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins that play a pivotal role in the detoxification of xenobiotics, cellular metabolism and homeostasis. Induction or inhibition of CYP enzymes is a major mechanism that underlies drug-drug interactions. CYP enzymes can be transcriptionally activated by various xenobiotics and endogenous substrates through receptor-dependent mechanisms. CYP enzyme inhibition is a principal mechanism for metabolism- based drug-drug interactions. Many chemotherapeutic drugs can cause drug interactions due to their ability to either inhibit or induce the CYP enzyme system. Predictions based on in silico analyses followed by validation have identified several microRNAs that regulate CYPs. Genetic polymorphisms and epigenetic changes in CYP genes may be responsible for inter-individual and interethnic variations in disease susceptibility and the therapeutic efficacy of drugs. OBJECTIVE: The present review is a comprehensive compilation of cytochrome P450 structure, function, pharmacogenetics, pharmacoepigenetics and clinical significance. CONCLUSION: Knowledge about the substrates, inducers, and inhibitors of CYP isoforms, as well as the polymorphisms of CYP enzymes may be used as an aid by clinicians to determine therapeutic strategy, and treatment doses for drugs that are metabolized by CYP gene products.

A significant number of drugs and drug candidates in clinical development are halogenated structures. For a long time, insertion of halogen atoms on hit or lead compounds was predominantly performed to exploit their steric effects, through the ability of these bulk atoms to occupy the binding site of molecular targets. However, halogens in drug - target complexes influence several processes rather than steric aspects alone. For example, the formation of halogen bonds in ligand-target complexes is now recognized as a kind of intermolecular interaction that favorably contributes to the stability of ligand-target complexes. This paper is aimed at introducing the fascinating versatility of halogen atoms. It starts summarizing the prevalence of halogenated drugs and their structural and pharmacological features. Next, we discuss the identification and prediction of halogen bonds in protein-ligand complexes, and how these bonds should be exploited. Interesting results of halogen insertions during the processes of hit-to-lead or lead-to-drug conversions are also detailed. Polyhalogenated anesthetics and protein kinase inhibitors that bear halogens are analyzed as cases studies. Thereby, this review serves as one guide for the virtual screening of libraries containing halogenated compounds and may be a source of inspiration for the medicinal chemists.

Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-κB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimers disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here. Keywords: Curcumin, molecular targets, transcription factors, growth factors, inflammatory cytokines, protein kinases, enzymes, diferuloylmethane, orange-yellow component, turmeric, polyphenol natural product, rhizome, anticancer, Alzheimer's disease, inflammatory illnesses, Ayurvedic medicine, pharmacological aspects, adhesion kinase, thioredoxin reductase, electrophile response element, preoliferator-activated receptor-gamma

The present paper reviews astrocyte pathology in major depressive disorder (MDD) and proposes that reductions in astrocytes and related markers are key features in the pathology of MDD. Astrocytes are the most numerous and versatile of all types of glial cells. They are crucial to the neuronal microenvironment by regulating glucose metabolism, neurotransmitter uptake (particularly for glutamate), synaptic development and maturation and the blood brain barrier. Pathology of astrocytes has been consistently noted in MDD as well as in rodent models of depressive-like behavior. This review summarizes evidence from human postmortem tissue showing alterations in the expression of protein and mRNA for astrocyte markers such as glial fibrillary acidic protein (GFAP), gap junction proteins (connexin 40 and 43), the water channel aquaporin-4 (AQP4), a calcium-binding protein S100B and glutamatergic markers including the excitatory amino acid transporters 1 and 2 (EAAT1, EAAT2) and glutamine synthetase. Moreover, preclinical studies are presented that demonstrate the involvement of GFAP and astrocytes in animal models of stress and depressive-like behavior and the influence of different classes of antidepressant medications on astrocytes. In light of the various astrocyte deficits noted in MDD, astrocytes may be novel targets for the action of antidepressant medications. Possible functional consequences of altered expression of astrocytic markers in MDD are also discussed. Finally, the unique pattern of cell pathology in MDD, characterized by prominent reductions in the density of astrocytes and in the expression of their markers without obvious neuronal loss, is contrasted with that found in other neuropsychiatric and neurodegenerative disorders.

Molecular docking is a process through which small molecules are docked into the macromolecular structures for scoring its complementary values at the binding sites. It is a vibrant research area with dynamic utility in structure-based drug-designing, lead optimization, biochemical pathway and for drug designing being the most attractive tools. Two pillars for a successful docking experiment are correct pose and affinity prediction. Each program has its own advantages and drawbacks with respect to their docking accuracy, ranking accuracy and time consumption so a general conclusion cannot be drawn. Moreover, users don't always consider sufficient diversity in their test sets which results in certain programs to outperform others. In this review, the prime focus has been laid on the challenges of docking and troubleshooters in existing programs, underlying algorithmic background of docking, preferences regarding the use of docking programs for best results illustrated with examples, comparison of performance for existing tools and algorithms, state of art in docking, recent trends of diseases and current drug industries, evidence from clinical trials and post-marketing surveillance are discussed. These aspects of the molecular drug designing paradigm are quite controversial and challenging and this review would be an asset to the bioinformatics and drug designing communities.

In the context of OA disease, NF-kappaB transcription factors can be triggered by a host of stress-related stimuli including pro-inflammatory cytokines, excessive mechanical stress and ECM degradation products. Activated NF-kappaB regulates the expression of many cytokines and chemokines, adhesion molecules, inflammatory mediators, and several matrix degrading enzymes. NF-kappaB also influences the regulated accumulation and remodeling of ECM proteins and has indirect positive effects on downstream regulators of terminal chondrocyte differentiation (including beta-catenin and Runx2). Although driven partly by pro-inflammatory and stress-related factors, OA pathogenesis also involves a "loss of maturational arrest" that inappropriately pushes chondrocytes towards a more differentiated, hypertrophic-like state. Growing evidence points to NF-kappaB signaling as not only playing a central role in the pro-inflammatory stress-related responses of chondrocytes to extra- and intra-cellular insults, but also in the control of their differentiation program. Thus unlike other signaling pathways the NF-kappaB activating kinases are potential therapeutic OA targets for multiple reasons. Targeted strategies to prevent unwanted NF-kappaB activation in this context, which do not cause side effects on other proteins or signaling pathways, need to be focused on the use of highly specific drug modalities, siRNAs or other biological inhibitors that are targeted to the activating NF-kappaB kinases IKKalpha or IKKbeta or specific activating canonical NF-kappaB subunits. However, work remains in its infancy to evaluate the effects of efficacious, targeted NF-kappaB inhibitors in animal models of OA disease in vivo and to also target these strategies only to affected cartilage and joints to avoid other undesirable systemic effects.

Drugs derived from natural resources represent a significant segment of the pharmaceutical market as compared to randomly synthesized compounds. It is a goal of drug development programs to design selective ligands that act on single disease targets to obtain highly effective and safe drugs with low side effects. Although this strategy was successful for many new therapies, there is a marked decline in the number of new drugs introduced into clinical practice over the past decades. One reason for this failure may be due to the fact that the pathogenesis of many diseases is rather multi-factorial in nature and not due to a single cause. Phytotherapy, whose therapeutic efficacy is based on the combined action of a mixture of constituents, offers new treatment opportunities. Because of their biological defence function, plant secondary metabolites act by targeting and disrupting the cell membrane, by binding and inhibiting specific proteins or they adhere to or intercalate into RNA or DNA. Phytotherapeutics may exhibit pharmacological effects by the synergistic or antagonistic interaction of many phytochemicals. Mechanistic reasons for interactions are bioavailability, interference with cellular transport processes, activation of pro-drugs or deactivation of active compounds to inactive metabolites, action of synergistic partners at different points of the same signalling cascade (multi-target effects) or inhibition of binding to target proteins. “-Omics” technologies and systems biology may facilitate unravelling synergistic effects of herbal mixtures. Keywords: Phytotherapy, phytomedicine, phytochemicals, herbal medicinal products, natural products, synergy, antagonism, galanthamine, artemisinin, hormesis, Nrf2, CREB, UDP-glucuronyl transferases, sulfotransferases, Berberine, Berberis, HMP, molecules, Omics, Scutellaria baicalensis, Dioscorea sp, Hypericum perforatum, St. John's wort, Hyperforin, GABA, Ginkgo, Ginkgo biloba, Willow, Salix alba, Marihuana, Cannabis sativa, Licorice, Glycyrrhiza glabra, Ginger, Zingiber officinalis, Kava-Kava, Piper methysticum, Stinging Nettle, Urtica dioica, Sabal serrulata, Serenoa repens, Devil's Claw, Harpagophytum procumbens, Arnica, Arnica montana, metalloproteinase, (MMP)1, Flavonoids, Artemisia annua, Lycopene, Isoflavones, Polyphenols

Nanomedicine involves the use of nanoparticles for therapeutic and diagnostic purposes. During the past two decades, a growing number of nanomedicines have received regulatory approval and many more show promise for future clinical translation. In this context, it is important to evaluate the safety of nanoparticles in order to achieve biocompatibility and desired activity. However, it is unwarranted to make generalized statements regarding the safety of nanoparticles, since the field of nanomedicine comprises a multitude of different manufactured nanoparticles made from various materials. Indeed, several nanotherapeutics that are currently approved, such as Doxil and Abraxane, exhibit fewer side effects than their small molecule counterparts, while other nanoparticles (e.g. metallic and carbon-based particles) tend to display toxicity. However, the hazardous nature of certain nanomedicines could be exploited for the ablation of diseased tissue, if selective targeting can be achieved. This review discusses the mechanisms for molecular, cellular, organ, and immune system toxicity, which can be observed with a subset of nanoparticles. Strategies for improving the safety of nanoparticles by surface modification and pretreatment with immunomodulators are also discussed. Additionally, important considerations for nanoparticle safety assessment are reviewed. In regards to clinical application, stricter regulations for the approval of nanomedicines might not be required. Rather, safety evaluation assays should be adjusted to be more appropriate for engineered nanoparticles.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer related deaths in the world with an estimated number of 1.8 million new cases and about 881,000 deaths worldwide in 2018. The epidemiology of CRC varies significantly between different regions in the world as well as between different age, gender and racial groups. Multiple factors are involved in this variation, including risk factor exposure, demographic variations in addition to genetic susceptibility and genetic mutations and their effect on the prognosis and treatment response. In this mini-review, we discuss the recent epidemiological trend including the incidence and mortality of colorectal cancer worldwide and the factors affecting these trends.

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BACKGROUND: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSION: 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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSION: 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.

INTRODUCTION: 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. METHOD: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSION: 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.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSION: 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.

INTRODUCTION/OBJECTIVE: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSION: Further investigation into the role of HNF4-α in tumor biology is encouraged.

Introduction: 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. Methods: 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. results: Docking analysis identified lopinavir and ritonavir as the only compounds meeting binding and stability criteria across all three APOL proteins. Both drugs demonstrated stable binding modes and favorable interaction energies during MD simulations. Ritonavir showed comparatively lower RMSD values and more confined conformational sampling, indicating enhanced structural stability. MM/GBSA calculations confirmed negative binding free energies for all complexes, with APOL4–ritonavir exhibiting the most favorable binding profile. ADMET analysis supported acceptable pharmacokinetic properties consistent with their approved clinical use. Results: 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. Discussion: 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. Conclusion: 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.

INTRODUCTION/OBJECTIVE: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSION: 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.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSION: The TYK2-Wnt5a axis is a promising, hypothesis-generating target in PsA; further mechanistic and clinical studies are needed to validate it therapeutically.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSION: 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.