Search Results (879)

This study combines ligand- and structure-based in silico strategies to predict the inhibitory activity of natural flavonoids on the Polo-Like Kinase-1 (PLK-1) enzyme as candidate anticancer agents. This enzyme participates in mitosis and is overexpressed in cancer cells. Furthermore, it has been shown to have important implications for tumor metastasis, and its inhibitors are attractive starting points for drug development. First, classification models are developed using linear discriminant analysis and a multilayer perceptron neural network. Models with accuracy greater than 80%, validated using standard statistical performance metrics and applicability domain, are used for virtual screening identifying four compounds as potential antitumor drugs. Subsequently, the identified compounds are evaluated using a molecular docking methodology to verify their binding mode and interactions with the catalytic domain of PLK-1. Finally, the integration of molecular dynamics simulations, at 300 ns, with Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) thermodynamic calculations demonstrates that the hydroxylation pattern of ring B in the flavonol scaffold is the fundamental chemical-structural determinant of electrostatic interactions and the architecture of water-mediated networks. Among the evaluated flavonoids, myricetin showed the most favorable overall computational profile, including the highest virtual-screening score and the most favorable mean MM/GBSA estimate, supporting its prioritization for experimental evaluation as a potential PLK-1 inhibitor. The integration of these approaches offers a robust methodological framework for proposing candidates with a higher probability of success, in subsequent stages of experimental validation, reducing time and costs in the early stages of drug development. Full article

Arterial Tortuosity Syndrome (ATS) is a rare autosomal recessive connective tissue disorder caused by pathogenic variants in SLC2A10, which encodes the facilitative glucose transporter GLUT10. Although its vascular features are well recognized, the molecular consequences of many truncating variants remain poorly understood. We report a patient with ATS carrying a homozygous nonsense variant, c.485G > A (p.Trp162Ter), identified by whole-exome sequencing. Quantitative real-time PCR assessed SLC2A10 expression, and integrated bioinformatic analyses (structural modeling, druggability prediction, transmembrane topology, molecular docking, and molecular dynamics) explored its structural impact. The patient presented with severe systemic arterial tortuosity, congenital cardiovascular anomalies, hernias, connective tissue abnormalities, and neurovascular involvement involving cerebral tortuosity and distal intracranial narrowing. Structural modeling revealed extensive truncation of GLUT10 and loss of multiple α-helical domains, with transmembrane helices reduced from twelve to five. Docking of nine known ligands showed weaker binding to the mutant, and Compound 892 bound most strongly to the wild type (−7.469 kcal/mol). Across 300 ns simulations, the mutant complex proved markedly less stable. qRT-PCR showed no significant transcript differences among patient, carriers, and controls. Our findings broaden the neurovascular spectrum of SLC2A10-related ATS and demonstrate that p.(Trp162Ter) severely disrupts GLUT10 architecture, topology, and ligand binding. Full article

Tetranectin (TN), also known as C-type lectin domain family 3 member B (CLEC3B), is a secreted glycoprotein originally identified through its high-affinity interaction with plasminogen. Although initially linked to fibrinolysis, TN is now increasingly recognized as an extracellular regulator associated with matrix remodeling, bone development, tissue repair, and disease-related proteolytic processes. Dysregulated TN expression has been reported in a broad range of pathological conditions, including cancer, cardiovascular disease, inflammatory disorders, and neurodegenerative states. In this review, we summarize current knowledge of TN with emphasis on its molecular architecture, ligand-binding properties, trimeric organization, and regulatory mechanisms. We further discuss its context-dependent biological functions, with particular attention to how tissue-specific and compartment-specific TN patterns may influence disease progression and clinical interpretation, especially in oncology. In addition, we evaluate the evidence supporting TN as a diagnostic and prognostic biomarker and consider its emerging therapeutic relevance. Finally, we outline the major challenges that currently limit clinical translation and highlight key directions for future investigation. Full article

Extracellular traps (ETs) are a novel host defense mechanism used to immobilize and eliminate invading microorganisms, and their formation depends on the recognition of foreign pathogens by membrane receptors. Previous studies have demonstrated that Vibrio splendidus flagellin can induce the release of ETs in coelomocytes of the sea cucumber Apostichopus japonicus, yet the underlying regulatory mechanism remains unclear. Here, we identify another Toll-like receptor (TLR) homolog, AjTLR2, in Apostichopus japonicus, which is composed of an extracellular LRR domain, a transmembrane domain, and an intracellular TIR domain. As a membrane receptor, AjTLR2 is upregulated upon infection with Vibrio splendidus AJ01, which is isolated from diseased Apostichopus japonicus. The extracellular LRR domain exhibits binding activity toward LPS, PGN, and MAN. In addition to these ligands, AjTLR2 recognizes flagellin C of AJ01 (AJ01-FliC), whereas other AjTLRs, such as AjToll and AjTLR3, do not. Further functional analysis reveals that knockdown of AjTLR2 results in a reduction in the typical weblike DNA structures of ETs, accompanied by a significant decrease in the expression of the ET-associated antimicrobial proteins H2A, H2B, and lysozyme. Furthermore, AjTLR2 knockdown similarly inhibits ET formation induced by recombinant AJ01-FliC protein. Mechanistically, the Apostichopus japonicus proto-oncogene tyrosine-protein kinase Src homolog (AjSRC), previously identified in our laboratory, is a downstream signaling molecule of AjTLR2 and is recruited via the TIR domain of AjTLR2. Knockdown of AjSRC also suppresses AJ01-FliC-induced ET formation. Collectively, our results indicate that the recruitment of AjSRC by AjTLR2 represents a potential regulatory pathway for AJ01-FliC induced ET generation. Full article

The restoration of mutant p53 stability is a highly sought-after strategy in targeted cancer therapy. This study presents a structure-based virtual screening and molecular dynamics approach to nominate FDA-approved drugs as candidate stabilizers of mutant p53 for downstream experimental validation. A virtual screening library of FDA-approved compounds was docked against three representative p53 mutants (7DHY, 7DHZ, and 7V97) to evaluate their binding potential. The prioritized candidates demonstrated consistent, multi-conformer binding affinities. Protein–ligand interaction profiling revealed that the candidate DB09280 possesses a highly dense interaction network, particularly against the V272M and R249S variants. Residue-level analysis of the G245S structural mutant showed that DB09280 uniquely engages His19, a crucial residue for zinc coordination, and forms stabilizing contacts with adjacent flexible loop residues, including ASN35 and PRO32. Subsequent 500 ns molecular dynamics simulations were consistent with DB09280 acting as a putative conformational clamp on the timescale sampled. The ligand-bound (holo) system exhibited substantially reduced global structural drift (RMSD) and attenuated local residue fluctuation (RMSF) within the core domain compared to the highly unstable apo state. Principal component analysis further indicated that DB09280 restricts the broad conformational sampling of the mutant into a stable, dominant basin within the sampled trajectory. Together, these computational findings nominate DB09280 as a promising candidate structural stabilizer of mutant p53 worthy of experimental follow-up. We emphasize that the in silico stabilization observed here is not equivalent to functional rescue of p53 transcriptional activity; biochemical, biophysical, and cell-based assays will be required to establish whether DB09280 restores wild-type-like DNA binding or tumor-suppressor function in mutant p53 contexts. Full article

The SARS-CoV-2 JN.1 subvariant has attracted attention due to the accumulation of mutations in the Spike (S) glycoprotein, particularly within the receptor-binding domain (RBD), contributing to the structural heterogeneity of the Spike protein. However, the extent to which conformational dynamics influence ligand-recognition patterns across functional Spike states remains insufficiently characterized. In this study, we applied a hierarchical computational framework combining homology modeling, molecular dynamics simulations, and molecular docking to determine whether conformational sampling modifies the location, accessibility, and recurrence of ligand-interaction regions in the JN.1 Spike protein. Closed, semi-closed, and open conformations were modeled and subjected to triplicate simulations, including an initial 100 ns phase followed by extended 200 ns simulations. Representative conformations were obtained by trajectory clustering and used for docking analyses. Two flavonoids, hesperitin-7-O-rutinoside (H7R) and flavanone-7-O-glucoside (F7G), were employed as structural probes to assess how ligand interaction patterns vary across conformational states. Comparative analyses revealed that conformational sampling modifies the location, accessibility and spatial distribution of ligand-interaction regions while generating distinct docking poses and recurrent interaction patterns not fully captured by static structural models. These findings highlight the importance of dynamics-informed structural ensembles for docking analyses in flexible viral proteins. Rather than predicting absolute binding affinities, this study provides an exploratory computational framework for evaluating ligand-recognition behavior in structurally dynamic viral systems. Full article

Cinnamoyl coenzyme A reductase (CCR) is the first rate-limiting enzyme in the monolignol-specific pathway and plays a pivotal role in lignin biosynthesis. However, CCR genes in Pinus yunnanensis remain uncharacterized, and their undefined substrate specificity further impedes mechanistic insights into lignin regulation while restricting strategies for wood property optimization. Using conserved domain and homology analysis, with a focus on the characteristic NAD(P)-binding motif (KNWYCYGK), we identified 12 CCR family members from the transcriptome data of P. yunnanensis. Phylogenetic analysis clustered the PyCCRs into two distinct clades: PyCCR1~6 fall into the CCR clade, while the remaining members form a CCR-like clade. In this study, twelve ORF regions of the P. yunnanensis CCR genes were cloned, and nine purified recombinant PyCCR proteins were obtained through prokaryotic expression. In vitro enzymatic assays demonstrated that PyCCR1, PyCCR2, PyCCR5, and PyCCR6 catalyzed the conversion of p-coumaroyl-CoA, feruloyl-CoA, and sinapoyl-CoA to p-coumaraldehyde, coniferaldehyde, and sinapaldehyde, respectively. Molecular docking of PyCCR1 to 6 with three substrates identified substrate-binding pocket domains. Within these domains, hydrogen bonds formed between ligands and residues in the R(X)5K motif of PyCCR1 to 6, whereas PyCCRL7 to 12 lacked the complete motif. RT-qPCR analysis showed tissue-specific expression patterns of the 12 genes across buds, stems, leaves, roots, and fruits. Collectively, these findings suggest that the presence of a complete R(X)5K motif may play a crucial role in maintaining the catalytic activity of PyCCRs. Our present study established a mechanistic foundation for elucidating lignin biosynthesis regulation in P. yunnanensis and offer genetic resources for improvement programs. Full article

Background/Objectives: Obesity and related metabolic diseases arise from an interplay of lipid overload, insulin resistance and oxidative stress. Acetyl-CoA carboxylase 2 (ACC2) controls malonyl-CoA production and thereby gates mitochondrial fatty-acid oxidation, placing it at the intersection of lipid handling and redox-sensitive metabolic dysfunction. Dietary antioxidants such as polyphenols, flavonoids and terpenoids are increasingly studied as modulators of these pathways, yet systematic prioritization of food-derived antioxidant compounds against defined metabolic targets remains challenging. We developed an integrated deep learning and structure-based workflow to prioritize FooDB compounds with predicted ACC2-binding potential. Methods: A curated set of 3983 ACC2 bioactivity records from ChEMBL 36 was used to train scaffold-split models, including graph neural-network and graph–Morgan fingerprint-fusion architectures. The calibrated ensemble screened 139,988 FooDB compounds; 200 candidates with predicted activity probability above 0.70 were docked against the ACC2 carboxyltransferase domain (PDB ID: 3FF6), and six prioritized complexes underwent 500 ns molecular dynamics and MM/GBSA analysis. Results: Redocking of the co-crystallized ligand reproduced the experimental pose (RMSD 1.2 Å). Although the highest-ranked screening hits were antioxidant terpenoids and alkaloids, docking-based prioritization from the top candidates selected six larger, more polar food-derived compounds, including glycosides and two nucleotide/cofactor-like conjugates, which showed docking scores from −7.47 to −6.65 kcal/mol versus −6.21 kcal/mol for the reference ligand. Glu539 emerged as a recurrent interaction hotspot. All candidates gave more favourable MM/GBSA binding free energies than the reference (ΔG = −22.52 kcal/mol), led by FDB029596 (−35.65), FDB021568 (−34.14) and FDB017807 (−33.87 kcal/mol). Conclusions: This workflow provides a reproducible framework for prioritizing food-derived compounds as candidate ACC2 binders relevant to obesity and metabolic disease, generating structurally supported hypotheses for biochemical and nutritional validation. The prioritized compounds are computational candidates only and require biochemical and cellular (experimental) validation before any ACC2-related biological relevance can be established. Full article

Carbohydrate-active enzymes (CAZymes) encoded by the human gut microbiome are central mediators of dietary glycan metabolism and host–microbe biochemical homeostasis. Among these, β-glucuronidases represent functionally pivotal hydrolases implicated in metabolism, intestinal physiology, and therapeutic modulation. The present study performs an integrative in silico structural and functional interrogation of β-glucuronidases derived from Acidobacterium capsulatum (3VNY), Bacteroides ovatus (6D8K), and Faecalibacterium prausnitzii (6ED2). An integrated computational framework encompassing physicochemical parameters profiling, hierarchical structural prediction, tertiary-structure validation, salt-bridge energetics, functional domain and motif annotation, protein–protein interaction reconstruction, ligand-binding thermodynamics via molecular docking, and residue-resolved non-covalent interaction network mapping using the Protein Contacts Atlas (PCA) was employed. Physicochemical analyses indicated that all enzymes are thermostable, intracellular, and hydrophilic, while secondary-structure organization revealed a functional balance between helix-mediated rigidity and coil-driven flexibility. Structural validation metrics identified 6ED2 as the most conformationally stable architecture, whereas 6D8K displayed enhanced functional complexity, including enriched motif composition, membrane-associated features, and superior ligand-binding affinity. Docking simulations highlighted castanospermine and calcium saccharate as the most favorable interacting ligands across enzyme variants. Importantly, PCA-based interaction analysis revealed distinct ligand-centered atomic contact networks, with immediate contact counts of 57 (3VNY), 32 (6D8K), and 41 (6ED2), providing residue-level insight into stabilization mechanisms and interaction topology beyond conventional docking metrics. Collectively, these findings establish a multidimensional computational framework linking structural stability, functional diversification, ligand recognition, and atomic interaction networks in gut microbial β-glucuronidases, thereby supporting future biochemical validation, microbiome-targeted therapeutics, and biotechnological or cosmeceutical applications. Full article

The Zona Pellucida (ZP) and its structural analogs are evolutionarily ancient extracellular matrix components. These are essential for oocyte protection, species-specific gamete recognition, and prevention of polyspermy across Metazoa. Defined by the conserved ZP-domain—comprising ZP-N and ZP-C subdomains—these glycoproteins self-assemble into fibrillar matrices through tightly regulated polymerization. Mechanisms of the regulated polymerization involve furin cleavage, disulfide bonding, and hydrophobic interactions. Once considered a vertebrate innovation, the canonical ZP-domain—defined by its bipartite ZP-N/ZP-C architecture, eight conserved cysteine residues, and capacity for matrix polymerization—is now recognized as an ancient metazoan extracellular module, with homologs identified in basal lineages including Porifera, Cnidaria, and Placozoa. While ZP-like sequences have been reported in choanoflagellates such as Salpingoeca rosetta, these lack the complete canonical features and are considered distant structural relatives rather than true ZP-modules. There they function in cell adhesion and tissue integrity, suggesting an origin predating the evolution of specialized reproductive coats. Previous phylogenetic analyses across 97 metazoan species have revealed that vertebrate ZP genes arose from ancestral duplications of the canonical ZP-module. Accordingly, they give rise to eight subfamilies (ZP1–ZP4, ZPD, ZPAX, ZPX, ZPY), with lineage-specific expansions, losses, and pseudogenization reflecting adaptations to diverse reproductive strategies. Positive selection in sperm-binding regions of ZP2 and ZP3 drives a rapid adaptive evolution. It underscores coevolutionary arms races with sperm ligands, contributing to reproductive isolation and speciation. In invertebrates such as abalone and insects, ZP-domain proteins mediate analogous functions through lineage-specific elaborations, including tandem repeats and domain shuffling. Post-translational modifications, particularly glycosylation, fine-tune sperm receptor specificity and matrix stability. The functional transition from a general protective barrier in early metazoans to a sophisticated gamete recognition interface in vertebrates exemplifies modular evolution. This synthesis highlights the domain-level deep homology of ZP-domain proteins as a foundational element of metazoan extracellular matrices, repurposed through gene duplication, neofunctionalization, and selection to meet the demands of evolving reproductive modes. These insights bridge evolutionary biology, reproductive medicine, and developmental genetics. However, major gaps remain, including unresolved orthology between vertebrate and invertebrate ZP genes, the relative contribution of glycans versus protein backbone in sperm recognition, and the lack of functional evidence for canonical ZP-domain proteins in insects. Future studies integrating glycoproteomics, single-cell transcriptomics, and CRISPR-based models are needed to resolve these questions. Full article

The increasing prevalence of multidrug-resistant Staphylococcus aureus (MRSA) has necessitated the development of alternative therapeutic strategies targeting bacterial virulence factors. This study employed an integrated in silico approach to identifying potential inhibitors of the iron-regulated surface determinant B Near-iron Transporter domain, a key protein involved in heme acquisition and pathogenicity. Virtual screening and molecular docking identified certain similarity-selected small molecules possessing strong binding affinities, with (4-(1-oxoisoindolin-2-yl)benzoic acid (TOP1) and (4-(2-oxochromen-3-yl)benzoic acid (TOP2) exhibiting the most favorable binding energies at −12.0 and −11.8 kcal/mol, respectively. Molecular dynamics simulations over 200 ns confirmed stable protein–ligand interactions that yielded reduced structural fluctuations in ligand-bound complexes when compared with the apo form. Molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) analysis revealed that van der Waals interactions were the primary contributors to binding, with TOP1 showing a more favorable overall binding energy. Drug-likeness and pharmacokinetic predictions indicated compliance with Lipinski’s rule of five and moderate bioavailability, although limited intestinal absorption was observed. Toxicity predictions indicated that both compounds are non-mutagenic but may exhibit hepatotoxicity. Notably, TOP1 exhibited potential nephrotoxicity, cardiotoxicity, and carcinogenicity, whereas TOP2 demonstrated a more favorable safety profile. These findings highlight a trade-off between binding affinity and safety, suggesting that TOP2 emerged as a computationally prioritized candidate for future experimental validation. Because the present findings represent computational predictions only, further orthogonal computational analyses and experimental studies are required to confirm the proposed binding modes, biological activity, and therapeutic potential of the identified compounds. Full article

Selective androgen receptor modulators (SARMs) are commonly described as tissue-selective anabolic agents, yet the extent to which this selectivity is reflected at the level of receptor-binding energetics remains uncertain. This study evaluated the receptor interaction profiles of the steroidal SARM YK11 and the nonsteroidal SARM ostarine across five steroid hormone nuclear receptors. Flexible molecular docking was performed with AutoDock 4.2 against the androgen (AR), estrogen (ER), progesterone (PR), glucocorticoid (GR), and mineralocorticoid (MR) receptors, using testosterone, estradiol, progesterone, cortisol, and aldosterone as endogenous reference ligands. Binding free energy, docking-derived inhibition constants, intermolecular interaction energies, conformational sampling, and two-dimensional interaction maps were analyzed. Ostarine showed favorable binding across all receptor systems, with binding energies ranging from −10.42 to −12.05 kcal/mol and no pronounced energetic preference for the androgen receptor. YK11 displayed stronger predicted binding, particularly toward the glucocorticoid, progesterone, and androgen receptors, with a docking energy trend of GR > PR > AR > MR > ER. Interaction analysis revealed conserved polar anchoring residues across receptor pockets, together with scaffold-specific contacts that may explain cross-receptor compatibility. These findings indicate that, within the AutoDock 4.2 flexible docking framework applied in this study, docking-derived binding energies primarily describe thermodynamic compatibility with nuclear receptor ligand-binding domains and should not be interpreted as direct predictors of functional SARM tissue selectivity. The observed discordance between predicted receptor affinity and the established tissue-selective pharmacology of ostarine highlights the need for caution when using single-method docking workflows to infer selectivity among closely related steroid hormone receptors. The novelty of this study lies in demonstrating, using a defined AutoDock 4.2-based comparative protocol, that receptor-binding energetics alone do not recapitulate the functional tissue-selective behavior attributed to SARMs. Full article

Diabetes mellitus remains a major metabolic disorder requiring the development of new and effective α-glucosidase inhibitors. The present study aimed to identify, design, and optimize novel 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-α]pyrimidine derivatives with promising inhibitory activity against the α-glucosidase enzyme using a comprehensive in silico strategy. Approximately 300 molecular descriptors were calculated to characterize a dataset of 32 compounds (Peytam et al.) and to investigate the structural factors governing their biological activity. Based on these descriptors, a multiple linear regression model was developed to predict the inhibitory activities of the compounds against alpha-glucosidase. The developed model demonstrated satisfactory predictive performance and was internally and externally validated to ensure its accuracy, robustness, and reproducibility. In addition, the applicability domain analysis confirmed the reliability of the predictions. Using the validated QSAR model, seven new derivatives were designed with predicted pIC₅₀ values exceeding the maximum activity of the parent compounds. The leverage analysis demonstrated that all newly designed compounds were located within the applicability domain of the model, supporting the reliability of the predictions. To further evaluate their inhibitory potential, molecular docking studies were performed to investigate the interactions between the designed compounds and the α-glucosidase active site. The docking results revealed favorable binding interactions comparable to those reported for known α-glucosidase inhibitors. Furthermore, ADMET analysis indicated generally favorable pharmacokinetic properties, although potential CYP3A4 inhibition-related pharmacokinetic risks were identified and discussed. Molecular dynamics simulations, including replicated runs and MM/GBSA binding free energy calculations, confirmed the stability of the most promising protein–ligand complexes throughout the simulation period. In conclusion, this study proposes a robust and integrated computational workflow combining descriptor generation, QSAR modeling, applicability domain analysis, molecular docking, ADMET prediction, and molecular dynamics simulations for the rational design of potential α-glucosidase inhibitors. The findings highlight the therapeutic potential of the designed derivatives and provide a valuable in silico framework for the future development of antidiabetic agents. Full article

Background: Ferrocene-containing compounds have gained attention in medicinal chemistry due to their unique redox and structural properties. This study investigates ferrocene-based analogues of imatinib and nilotinib to define their binding determinants within the ABL1 kinase domain using an integrated in silico approach, in relation to their previously reported cytotoxic activity. Methods: Ligand geometries were optimized at the B3LYP/def2-TZVP level with D3(BJ) dispersion and SMD solvation. Molecular docking against ABL1 (PDB ID: 2HYY) was performed using Glide SP, validated by re-docking and enrichment screening. Docked poses were refined using MM-GBSA (Prime, VSGB 2.1/OPLS4). The most active compounds (9 and 15a), together with the inactive control 15e, were subjected to three independent 500 ns molecular dynamics simulations (Desmond, OPLS4), followed by trajectory analysis including RMSD, RMSF, radius of gyration, SASA, and polar surface area. Results: Compounds 9 and 15a maintained stable binding within the ATP-binding pocket despite lacking the canonical hinge interaction with Met318, indicating hinge-independent binding. Their binding was mainly driven by interactions with Asp381 (DFG motif) and cation–π contacts with Lys271. In contrast, the compound 15e showed unstable binding, increased conformational flexibility, reduced pocket burial, and loss of key stabilizing interactions. Active compounds also preserved stable P-loop dynamics, with Tyr253 engagement suggesting a role in loop stabilization. Compound 9 exhibited the most constrained and reproducible binding mode among all analogues. Conclusions: Ferrocene-based analogues can sustain stable ABL1 binding via non-classical interaction networks independent of hinge recognition. The clear distinction between active compounds and the inactive analogue 15e supports the robustness of the proposed binding mode and provides a structural basis for their reported cytotoxic activity. These findings support further experimental evaluation of ferrocene-containing scaffolds as potential BCR-ABL1 inhibitors. Full article

CXCL8, a pro-inflammatory chemokine, which can be induced by TNF-α or IL-1, is responsible for the recruitment and activation of neutrophils. Chemokines interact with glycosaminoglycans on endothelial cells and are thus protected from degradation and sequestration, holding them in an optimal position for recruiting immune cells. Inhibiting the interaction of chemokines with their glycosaminoglycan co-receptors represents an attractive approach for the treatment of chemokine-mediated diseases. Two polyketide-pyrone compounds, PA501 and PA502 were synthesized, which bind to CXCL8 with affinities higher than the natural glycosaminoglycan ligand heparan sulfate, and in a similar range as heparin. Significant structural changes were induced in the chemokine by interacting with the two compounds, as expressed in fluorescence and far-UV CD experiments. In filter binding assays, both compounds were found to displace heparan sulfate efficiently from CXCL8, with PA501 displaying the highest competition efficacy. Using a C-terminally truncated form of the chemokine, CXCL81-58, which lacks the main glycosaminoglycan-binding α-helical domain, the two compounds are suggested to use—to a varying degree—different binding sites on the protein, which have also been proposed for the natural heparan sulfate ligand. In a transmigration assay, PA501 and PA502 exhibited dose-dependent modulation of CXCL8-induced neutrophil mobilization and migration. The compounds PA501 and PA502 may thus be regarded as early novel lead compounds in the quest for anti-inflammatory, chemokine-targeting drugs. Full article