Search Results (2,199)

Background: Human noroviruses are the leading cause of foodborne gastroenteritis worldwide. Accumulating evidence suggests that food matrices containing fucosylated or histo-blood group antigen (HBGA)-like glycans may facilitate viral attachment and persistence, yet the molecular mechanisms underlying these interactions remain unclear. Methods: In this study, we performed a comparative computational analysis of norovirus–glycan interactions by integrating AlphaFold3-based structure prediction, molecular docking, and molecular dynamics simulations. A total of 182 P-domain models representing all genotypes across five human norovirus genogroups (GI, GII, GIV, GVIII, and GIX) were predicted and docked with a lettuce-derived core-fucosylated hexasaccharide (H₂N₂F₂) previously identified by our group. The three complexes exhibiting the most favorable docking energies were further examined using 40 ns molecular dynamics simulations, followed by MM/GBSA binding free energy calculations and per-residue decomposition analyses. Results: Docking results indicated that the majority of modeled P proteins were able to adopt energetically favorable interaction poses with H₂N₂F₂, with predicted binding energies ranging from −3.7 to −7.2 kcal·mol⁻¹. The most favorable docking energies were observed for GII.6_S9c_KC576910 (−7.2 kcal·mol⁻¹), GII.3_MX_U22498 (−7.1 kcal·mol⁻¹), and GII.4_CARGDS11182_OR700741 (−6.8 kcal·mol⁻¹). Molecular dynamics simulations suggested stable ligand engagement within canonical HBGA-binding pockets, with recurrent residues such as Asp374, Gln393, and Arg345 contributing to electrostatic and hydrophobic interactions, consistent with previously reported HBGA-binding motifs. MM/GBSA analyses revealed comparatively favorable binding tendencies among these complexes, particularly for globally prevalent genotypes including GII.3, GII.4, and GII.6. Conclusions: This work provides a large-scale structural and energetic assessment of the potential interactions between a naturally occurring lettuce-derived fucosylated hexasaccharide and human norovirus P domains. The results support the notion that core-fucosylated food-associated glycans can serve as interaction partners for diverse norovirus genotypes and offer comparative molecular insights into glycan recognition patterns relevant to foodborne transmission. The integrative AlphaFold3–docking–dynamics framework presented here may facilitate future investigations of virus–glycan interactions within food matrices. Full article

ORF8 is the second most mutated protein in SARS-CoV-2. It can form oligomers such as trimers and can bind to the IL-17RA/RC receptor. To understand the possible role of ORF8 in SARS-CoV-2, the first step of this study involved predicting the ORF8 trimer structure and the complex structure of the ORF8 monomer bound to the IL-17RA receptor using docking and molecular dynamics simulation methods. It was found that ORF8 molecules bound to the central ORF8 molecule through covalent and noncovalent interactions exhibit similar RMSD and RMSF values as the central ORF8 molecule and form a similar buried surface area, but display different numbers of hydrogen bonds and varying dynamic correlations. Additionally, trimer formation increases the dynamic correlation of the noncovalently bound ORF8 unit. ORF8 can bind with the IL-17RA receptor stably. Regions on ORF8, including C25–I47, L60–S67, T80–C90, and S103–E110, and regions on IL-17RA, including L1–H63 and D122–M165, are involved in the binding interface of the complex. ORF8 becomes less rigid when bound to IL-17RA than in its monomer, dimer, and trimer forms. Based on dihedral angle correlation predictions, binding of ORF8 to IL-17RA reduces internal correlations within ORF8 while strengthening correlations within IL-17RA. The G50–T80 region of ORF8 appears to be critical for interaction with IL-17RA, and the L1–V150 region of IL-17RA should be critical for its dynamics once bound to ORF8. These results help elucidate the structure and dynamics of ORF8 in SARS-CoV-2. Full article

A series of novel granatane–triazole hybrid molecules was designed, synthesized, and evaluated as dual acetylcholinesterase (AChE) and β-secretase 1 (BACE1) inhibitors. The compounds were obtained through a convergent synthetic route involving azide formation, triazole construction via dipolar cycloaddition, and final coupling with a granatane scaffold to give a pseudopelletierine (3-granatanone) analogue. In vitro assays demonstrated that all target compounds inhibited both AChE and BACE1. Molecular docking and molecular dynamics simulations revealed stable interactions with key catalytic residues, suggesting distinct binding modes compared to reference ligands. QSAR-based pharmacokinetic predictions indicated favorable blood–brain barrier permeability and compliance with key drug-likeness filters. These findings identify granatane–triazole hybrids as promising multi-target directed ligand (MTDL) candidates with potential for further optimization in the search for new anti-Alzheimer therapeutics. Full article

Intrinsically disordered regions enable transcription factors (TFs) to undergo structural changes upon ligand binding, facilitating the transduction of environmental signals into gene expression. In this study, we applied molecular modeling methods to explore the hypothesis that unstructured inter-domain and subdomain linkers in bacterial TFs can function as sensors for carbohydrate signaling molecules. We combined molecular dynamics simulations and carbohydrate docking to analyze six repressors with GntR-type DNA-binding domains, including UxuR, GntR and FarR from Escherichia coli, as well as AraR, NagR and YydK from Bacillus subtilis. Protein models obtained from different time points of the dynamic simulations were subjected to sequential carbohydrate docking. We found that the inter-domain linker of the UxuR monomer binds D-fructuronate, D-galacturonate, D-glucose, and D-glucuronate with an affinity comparable to nonspecific interactions. However, these ligands formed multimolecular clusters, a feature absent in the UxuR dimer, suggesting that protein dimerization may depend on linker occupancy by cellular carbohydrates. D-glucose interacted with linkers connecting subdomains of the LacI/GalR-type E-domains in GntR and AraR, forming hydrogen bonds that connected distant structural modules of the proteins, while in NagR, FarR and YydK, it bridged the inter-domain linkers and a β-sheet within the HutC-type E-domains. Hence, our results establish flexible linkers as pivotal metabolic sensors that directly integrate nutritional cues to alter gene expression in bacteria. Full article

Background/Objectives: Osteoporosis is a multifactorial skeletal disorder in which chronic inflammation, dysregulated cytokine signaling, and metabolic imbalance contribute to excessive bone resorption and impaired bone formation. Asiatic acid has demonstrated bone-protective effects, but its molecular mechanisms in osteoporosis remain incompletely understood. This study aimed to investigate the anti-osteoporotic mechanisms of asiatic acid using an integrative in silico strategy. Methods: Network pharmacology analysis was performed to identify osteoporosis-related molecular targets of asiatic acid. Molecular docking was used to predict the binding modes and affinities between asiatic acid and its target proteins. Molecular dynamics simulation was used to assess the structural stability and interaction persistence of the asiatic acid–protein complex. Results: Network pharmacology identified 135 overlapping targets between asiatic acid and osteoporosis, with IL-6, STAT3, PPARG, and NFKB1 emerging as key hubs. KEGG analysis indicated the PPAR signaling pathway as a potential mechanism underlying the anti-osteoporotic effect. Molecular docking showed strong binding energies of asiatic acid with all predicted target proteins, with the highest affinity observed for IL-6, involving key residues ASN61, LEU62, GLU172, LYS66, and ARG168. Consistently, molecular dynamics simulation confirmed stable binding of asiatic acid to IL-6, with persistent interactions with ASN61, LYS66, LEU62, LEU64, and GLN154 mediated by hydrogen bonds, water bridges, and hydrophobic interactions. Conclusions: This integrative in silico study provides mechanistic insight into the potential anti-osteoporotic actions of asiatic acid, implicating IL-6 as a plausible upstream molecular target. These results establish a robust mechanistic framework for future translational studies exploring asiatic acid as a natural therapeutic candidate for osteoporosis. Full article

Background: Saffron (Crocus sativus L.) corms, often discarded as agricultural by-products, are a promising and sustainable source of bioactive metabolites with potential therapeutic relevance. However, their anticancer potential remains largely underinvestigated. Objectives: This study aimed to compare the phytochemical composition of hydroethanolic extracts from fresh (HEEF) and stored (HEES) saffron corms and to evaluate their anticancer effectiveness against colorectal cancer cells. Methods: Phytochemical profiling was performed using HPLC-ESI-QTOF-MS/MS. Cytotoxicity against T84 and SW480 colorectal cancer cell lines was determined by the crystal violet assay. Apoptosis-related protein modulation was assessed by Western blotting. Additionally, molecular docking, molecular dynamics simulations, and MM/GBSA calculations were used to investigate ligand–target binding affinities and stability. Results: Both extracts contained diverse primary and secondary metabolites, including phenolic acids, flavonoids, triterpenoids, lignans, anthraquinones, carotenoids, sugars, and fatty acids. HEES showed higher relative abundance of key bioactive metabolites than HEEF, which was enriched mainly in primary metabolites. HEES showed significantly greater dose-dependent cytotoxicity, particularly against SW480 cells after 24 h (IC₅₀ = 34.85 ± 3.35). Apoptosis induction was confirmed through increased expression of caspase-9 and p53 in T84 cells. In silico studies revealed strong and stable interactions of major metabolites, especially 3,8-dihydroxy-1-methylanthraquinone-2-carboxylic acid with COX2 and crocetin with VEGFR2. Conclusions: Stored saffron corms possess a richer bioactive profile and show enhanced anticancer effects in vitro compared with fresh saffron corms, suggesting that they may represent a promising source of compounds for the future development of colorectal cancer therapeutics. Full article

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disease characterized primarily by intravascular hemolysis, thrombosis, and bone marrow failure. Complement inhibitors are commonly used in clinical treatment and show limited efficacy, highlighting the urgent need to identify new therapeutic targets and explore alternative treatment strategies to provide theoretical guidance for clinical practice. Methods: We established a PNH cell model and constructed an miRNA–mRNA regulatory network to identify key miRNAs and core target genes. Single-cell sequencing data were analyzed to further clarify the critical genes. Finally, integrated drug database analysis identified potential therapeutic agents for PNH, which were validated by molecular docking and molecular dynamics simulations. Results: Using CRISPR/RNP technology, we successfully constructed a PIGA-knockout (PIGA-KO) THP-1 cell model. Differential expression analysis identified 1979 differentially expressed mRNAs (DEmRNAs) and 97 differentially expressed miRNAs (DEmiRNAs). The multiMiR package in R was used to predict the target genes of DEmiRNAs, from which those experimentally validated through dual-luciferase reporter assays were selected. After integration with the DEmRNAs, an miRNA–mRNA regulatory network was constructed, comprising 26 miRNAs and 38 mRNAs. Subsequent miRNA pathway enrichment analysis identified hsa-miR-23a-3p as a key miRNA, with CXCL12, CXCL8, HES1, and TRAF5 serving as core target genes. The integration of single-cell sequencing datasets (PRJNA1061334 and GSE157344) was performed, followed by cell communication and enrichment analysis. This approach, combined with clinical relevance, identified the neutrophil cluster as the key cluster. Intersection analysis of neutrophil cluster differential analysis results with key modules from hdWGCNA further clarified the critical genes. Drug prediction using EpiMed, CMap, and DGIdb identified Leflunomide, Dipyridamole, and Pentoxifylline as potential therapeutic agents. Molecular docking and molecular dynamics simulations showed stable binding of these potential drugs to the critical molecules, indicating a viable molecular interaction foundation. Conclusions: Leflunomide, Dipyridamole, and Pentoxifylline may serve as promising therapeutic agents for PNH, and the hsa-miR-23a-3p/CXCL8 regulatory axis could play a pivotal role in the pathogenesis and progression of PNH. Full article

Background/Objectives: Cancer-associated fibroblasts (CAFs) are key stromal mediators of breast tumor progression and therapy resistance. Carvacrol, a dietary monoterpenic phenol, exhibits antiproliferative activity in cancer cells, but its effects on primary human breast CAFs remain unclear. This study aimed to determine whether carvacrol selectively induces mitochondria-related apoptotic signaling in breast CAFs while sparing normal fibroblasts (NFs). Methods: Primary fibroblast cultures were established from invasive ductal carcinoma tissues (CAFs, n = 9) and nonmalignant breast tissues (NFs, n = 5) and validated by α-SMA and FAP immunofluorescence. Cells were exposed to 400 μM carvacrol. Apoptosis was assessed by TUNEL assay and BAX/BCL-XL Western blotting. Changes in signaling pathways were evaluated by analyzing PPARα/NF-κB, sirtuin (SIRT1, SIRT3), autophagy-related markers (LAMP2A, p62), and matrix metalloproteinases (MMP-2, MMP-3). In silico molecular docking and 100-ns molecular dynamics simulations were performed to examine interactions between carvacrol and caspase-3 and caspase-9. Results: Carvacrol induced a pronounced, time-dependent apoptotic response in CAFs, with TUNEL-based viability declining to approximately 10% of control levels by 12 h and a marked increase in the BAX/BCL-XL ratio. In contrast, NFs exhibited minimal TUNEL positivity and no significant change in BAX/BCL-XL. In CAFs, but not NFs, carvacrol reduced PPARα expression and NF-κB nuclear localization, increased SIRT1 and SIRT3 levels, selectively suppressed MMP-3 while partially normalizing MMP-2, and altered autophagy-related markers (decreased LAMP2A and accumulation of p62), consistent with autophagic stress and possible impairment of autophagic flux. Computational analyses revealed stable carvacrol binding to caspase-3 and caspase-9 with modest stabilization of active-site loops, supporting caspase-dependent, mitochondria-related apoptosis. Conclusions: Carvacrol selectively targets breast cancer-associated fibroblasts by inducing mitochondria-related apoptotic signaling while largely sparing normal fibroblasts. This effect is accompanied by coordinated modulation of PPARα/NF-κB, sirtuin, autophagy, and MMP pathways. These findings support further evaluation of carvacrol as a microenvironment-directed adjunct in breast cancer therapy. Full article

The oleic-to-linoleic acid ratio (O/L) is a key determinant of oil quality, yet its molecular basis in Cornus wilsoniana remains unclear. Here, we combined fatty-acid profiling with molecular dynamics (MD) simulations and catalytic tunnel analysis to compare four annotated FAD2 homologs. Sequence alignment revealed a major variable segment at residues 160–185, including a small deletion in CW09G04700 and an extensive deletion in CW04G07690. Docking against oleic acid supported excluding CW04G07690 due to weak binding. Eighty-nanosecond MD simulations showed that CW02G01750 and CW09G27260 rapidly converged to stable conformational ensembles with lower core flexibility, whereas CW09G04700 exhibited higher internal mobility around residues 180–220. CAVER analysis further indicated increasingly accessible catalytic tunnels for CW02G01750 and CW09G27260 during simulation, while CW09G04700 displayed transient tunnel narrowing accompanied by ligand conformational readjustments. These results nominate CW02G01750 as a leading structural candidate among C. wilsoniana FAD2 homologs and highlight access-pathway dynamics as a mechanistic feature potentially contributing to O/L formation. Full article

Infectious diseases remain a persistent global health threat, intensified by the rapid emergence of antibiotic-resistant pathogens. Despite the transformative impact of antibiotics, the escalating resistance crisis underscores the urgent need for alternative therapeutic approaches. Antimicrobial peptides (AMPs) have emerged as promising candidates due to their broad-spectrum antimicrobial and immunomodulatory activities. The present study investigated 82 honey bee antimicrobial peptides (BAMPs) representing seven families: abaecin, apamin, apisimin, apidaecin, defensin, hymenoptaecin, and melittin among eight honey bee species. Immunoinformatics analyses identified five peptides (P15450, A0A2A3EK62, Q86BU7, C7AHW3, and I3RJI9A) with high antigenicity and non-allergenic profiles. Structural modeling, molecular docking with TLR3 and TLR4-MD2, and molecular dynamics simulations revealed stable receptor-peptide interactions and favorable binding energetics, further supported by silico immune simulations. Overall, these findings suggest that the selected BAMPs exhibit strong immunogenic potential and may serve as effective adjuvants or carrier molecules in subunit vaccine design against drug-resistant pathogens; however, further experimental validation is essential to confirm their safety and immunological efficacy. Full article

Organic and inorganic peroxides can induce intracellular redox homeostasis. In this study, a γ-cyclodextrin/genistein inclusion complex (γ-CD/GEN) was constructed to systematically elucidate the molecular mechanism by which it catalyzes GPx4-mediated peroxide reduction. The results indicate that the incorporation of γ-CD effectively disrupts the aggregated state of GEN, achieving an encapsulation efficiency (EE) exceeding 40%. Surface-enhanced Raman spectroscopy (SERS) analysis reveals significant differences in the catalytic behavior of γ-CD/GEN toward cumene hydroperoxide (CHP) and hydrogen peroxide (H₂O₂): the reduction efficiency of CHP depends on both the concentration of γ-CD/GEN and GPx4, whereas the reduction of H₂O₂ is primarily regulated by the concentration of γ-CD/GEN. Isotope effect studies demonstrate that the reduction of CHP relies more on radical-initiated reactions, while the reduction of H₂O₂ involves proton transfer, with the differences in reduction rates correlating with their respective redox mechanisms. Molecular docking and molecular dynamics simulations further confirm that γ-CD/GEN can stably bind to the Sec (Cys)-46 site in the active center of GPx4, thereby enhancing its catalytic activity. This study provides a theoretical basis for the development of antioxidant strategies based on the precise regulation of enzyme activity. Full article

We present a computational study that precedes the potential interactions between SARS-CoV-2 helicase (NSP13) and selected host proteins implicated in chaperone-assisted folding and polyamine metabolism. Using structure-based modelling and protein–protein docking (BioLuminate v4.6), followed by all-atom molecular dynamics (MD) simulations (GROMACS v2018.6), and comparative MM-GBSA scoring (HawkDock v2), we evaluated the stability and interface properties of NSP13 complexes with cytosolic heat shock proteins; heat shock protein 40 (HSP40), heat shock protein 70 (HSP70), heat shock protein 90 (HSP90) and the polyamine biosynthesis enzyme ornithine decarboxylase (ODC). Docking, MD, and interface analyses indicate distinct complex behaviours: HSP70-NSP13 complexes sampled compact conformations, HSP90-NSP13 ensembles displayed greater conformational heterogeneity but more favourable comparative MM-GBSA estimates, and ODC-NSP13 interfaces were comparatively well packed. Per-residue contact mapping identified a small set of recurrent NSP13 residues, Lys22 and Asn51, as putative interaction hotspots. The reported findings herein generate testable hypotheses about NSP13 recruitment of host chaperones and modulation of polyamine metabolism that may inform downstream experimental studies. Full article

Background: Due to chronic venous insufficiency, venous leg ulcers (VLUs) develop as chronic wounds characterized by impaired healing, persistent inflammation, and endothelial dysfunction. Nitrosative stress, mitochondrial damage, and tissue apoptosis caused by excess nitric oxide (NO) produced by iNOS in macrophages and fibroblasts are contributing factors in the chronic wound environment; therefore, pharmacological modulation of iNOS presents an attractive mechanistic target in chronic wound pathophysiology. Methods: Herein, we present the use of a structure-based computational strategy to assess the inhibition of tavaborole, a boron-based antifungal agent, against iNOS using human iNOS crystal structure (PDB ID: iNOS) by molecular docking using AutoDock 4.2, 500 ns simulation of molecular dynamics (MD), with equilibration within ~50 ns and analyses over full trajectory and binding free energy calculations through the MM-PBSA approach. Results: Docking studies showed favorable binding of tavaborole (–6.1 kcal/mol) in the catalytic domain, which stabilizes contacts with several key residues (CYS200, PRO350, PHE369, GLY371, TRP372, TYR373, and GLU377). MD trajectories for 1 ns showed stable structural configurations with negligible deviations (RMSD ≈ 0.44 ± 0.10 nm) and hydrogen bonding, and MM-PBSA analysis confirmed energetically favorable complex formation (ΔG_binding ≈ 18.38 ± 63.24 kJ/mol) similar to the control systems (L-arginine and 1400W). Conclusions: Taken together, these computational findings indicate that tavaborole can stably occupy the iNOS active site and interact with key catalytic residues, providing a mechanistic basis for further in vitro and ex vivo validation of its potential as an iNOS inhibitor to reduce nitrosative stress and restore endothelial homeostasis in venous leg ulcers, rather than direct therapeutic proof. Full article

Capsaicin, a naturally occurring polyphenol, is known to affect energy expenditure and muscle fatigue and modulate contractions in skeletal muscle. The L-type Ca²⁺ channels are known to be an important ion channel involved in the various muscle functions and the effect of capsaicin on the skeletal L-type Ca²⁺ channels is currently unknown. In this study, the effects of capsaicin and capsaicin analogs on depolarization-induced Ca²⁺ effluxes through L-type Ca²⁺ channels in transverse tubule membranes from rabbit skeletal muscle and L-type Ca²⁺ currents recorded using the whole-cell patch clamp technique in rat myotubes were examined. Capsaicin, in the concentration range of 3–100 µM, inhibited depolarization-induced Ca²⁺ effluxes. The effect of capsaicin was not reversed by TRPV1 antagonist SB-366791 (10 µM). While vanilloids (30 µM) including vanillin, vanillyl alcohol, and vanillylamine were ineffective, other capsaicinoids (30 µM) including dihydrocapsaicin, nonivamide, and nordihydrocapsaicin significantly inhibited Ca²⁺ effluxes, suggesting that hydrocarbon chains are required for inhibition. In rat myotubes, capsaicin inhibited L-type Ca²⁺ currents with an IC₅₀ value of 27.2 μM in the presence of SB-366791. Furthermore, in docking studies and molecular dynamic simulations, capsaicinoids with an aliphatic tail showed stronger binding and stable bent conformations in CaV1.1, forming hydrogen bonds with Ser1011 and Thr935 and hydrophobic/π–alkyl contacts with Phe1008, Ile1052, Met1366, and Ala1369, resembling the binding mode of amlodipine. In conclusion, the results indicate that the function of L-type Ca²⁺ channels in mammalian skeletal muscle was inhibited by capsaicin and capsaicin analogs in a TRPV1-independent manner. Full article

Background and Objectives: Many “food–medicine homologous traditional Chinese medicines (TCMs)” have been shown to delay vascular aging. In this study, we will select “food–medicine homologous TCMs” with the most potential to delay human-origin vascular aging and predict their core targets and mechanisms. Methods: Human-origin vascular-aging-related genes were screened from the NCBI and Aging Atlas databases. Candidate “food–medicine homologous TCMs” were initially filtered by constructing a protein–protein interaction network, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Key targets were validated in the Gene Expression Omnibus database and further screened by least absolute shrinkage and a selection operator. Finally, molecular docking and molecular dynamics simulations identified core targets. Results: Ten core “food–medicine homologous TCMs” with potential to delay human-derived vascular aging were identified: Crocus Sativus L., Glycyrrhiza uralensis Fisch., Chrysanthemum morifolium Ramat., Astragalus membranaceus (Fisch.) Bunge, Sophora japonica L., Hippophae rhamnoides L., Portulaca oleracea L., Lonicera japonica Thunb., Citrus aurantium L. var. amara Engl., and Morus alba L. Further analysis indicated that β-Carotene within these core “food–medicine homologous TCMs” may represent a potential active component targeting matrix metalloproteinase-1, with its action potentially linked to the interleukin-17 signaling pathway. The present study highlights the new hypothesis that immunosenescence (Th17/IL-17) is involved in vascular aging, suggesting that the top ten core “food–medicine homologous TCMs” may delay vascular aging by regulating immune cell function. Conclusions: The top ten “food–medicine homologous TCMs” provide potential candidates for functional products that delay vascular aging and provide computationally predicted mechanistic insights and a scientific basis for novel therapies. Full article