Search Results (1,421)

The glucagon-like peptide-1 receptor (GLP-1R), which belongs to the class B1 G protein-coupled receptor (GPCR) family, is an important target for treatment of metabolic disorders, including type 2 diabetes and obesity. The growing interest in GLP-1R-based therapies is driven by the development of various functional agonists as well as the huge commercial market. Thus, understanding the structural details of ligand-induced signaling are important for developing improved GLP-1R drugs. Here, we investigated the conformational dynamics of the receptor in complex with a selection of prototypical functional agonists, including CHU-128 (small molecule-biased), danuglipron (small molecule balanced), and Peptide 19 (peptide balanced), which exhibit unique, distinct binding modes and induced helix packing. Furthermore, our all-atom molecular dynamics (MD) simulations revealed atomic feature how different those ligands led to signaling pathway preference. Our findings offer valuable insights into the mechanistic principle of GLP-1R activation, which are helpful for the rational design of next-generation GLP-1R drug molecules. Full article

This story began half a century ago with the discovery of an unusually high presence of tryptophan (Trp, W) in transthyretin (TTR), one of the three carrier proteins of thyroid hormones. With the Trp-rich retinol-binding protein (RBP), TTR forms a plasma complex implicated in the delivery of retinoid compounds to body tissues. W has the lowest concentration among all AAs involved in the sequencing of human body proteins. The present review proposes molecular maps focusing on the ratio of W/AA residues found in the sequence of proteins involved in immune events, allowing us to ascribe the guidance of inflammatory processes as fully under the influence of W. Under the control of cytokine stimulation, plasma biomarkers of protein nutritional status work in concert with major acute-phase reactants (APRs) and with carrier proteins to release, in a free and active form, their W and hormonal ligands, interacting to generate hot spots affecting the course of acute stress disorders. The prognostic inflammatory and nutritional index (PINI) scoring formula contributes to identifying the respective roles played by each of the components prevailing during the progression of the disease. Glucagon demonstrates ambivalent properties, remaining passive under steady-state conditions while displaying stronger effects after cytokine activation. In developing countries, inappropriate weaning periods lead to toddlers eating W-deficient cereals as a staple, causing a dramatic reduction in the levels of W-rich biomarkers in plasma, constituting a novel nutritional deficiency at the global scale. Appropriate counseling should be set up using W implementations to cover the weaning period and extended until school age. In adult and elderly subjects, the helpful immune protections provided by W may be hindered by the surge in harmful catabolites with the occurrence of chronic complications, which can have a significant public health impact but lack the uncontrolled surges in PINI observed in young infants and teenagers. Biomarkers of neurodegenerative and neoplastic disorders measured in elderly patients indicate the slow-moving elevation of APRs due to rampant degradation processes. Full article

A novel ruthenium(II) complex, [RuCl₂(η⁶-p-cymene)(bph-κN)] (1), was synthesized and structurally characterized using FTIR and NMR spectroscopy. Density functional theory (DFT) calculations supported the proposed geometry and allowed for comparative analysis of experimental and theoretical spectroscopic data. The interaction of complex 1 with human serum albumin (HSA) and calf thymus DNA was investigated through fluorescence quenching experiments, revealing spontaneous binding driven primarily by hydrophobic interactions. The thermodynamic parameters indicated mixed quenching mechanisms in both protein and DNA systems. Ethidium bromide displacement assays and molecular docking simulations confirmed DNA intercalation as the dominant binding mode, with a Gibbs free binding energy of −34.1 kJ mol⁻¹. Antioxidant activity, assessed by EPR spectroscopy, demonstrated effective scavenging of hydroxyl and ascorbyl radicals. In vitro cytotoxicity assays against A375, MDA-MB-231, MIA PaCa-2, and SW480 cancer cell lines revealed selective activity, with pancreatic and colorectal cells showing the highest sensitivity. QTAIM analysis provided insight into metal–ligand bonding characteristics and intramolecular stabilization. These findings highlight the potential of 1 as a promising candidate for further development as an anticancer agent, particularly against multidrug-resistant tumors. Full article

The Inula japonica flower is traditionally used to alleviate lung inflammatory symptoms. While the therapeutic effect of the I. japonica flower on lung diseases has been suggested, the efficacy of the I. japonica flower in treating atopic dermatitis (AD) remains unknown. We investigated the effects of a water extract of the I. japonica flower (WEIF) on Dermatophagoides farinae extract (DfE)-induced AD-like inflammation in NC/Nga mice. Histological analysis of the epidermal structure, mast cell infiltration, and barrier protein expression were examined. Serum inflammatory mediator levels were assessed. To elucidate the regulatory pathway of WEIF, the effects of 1,5-dicaffeoylquinic acid (DCQA) and 1-O-acetylbritannilactone (ABL) in WEIF on the JAK/STAT pathway were evaluated in interferon-γ/tumor necrosis factor (TNF)-α-stimulated human adult epidermal keratinocytes. WEIF ameliorated DfE-induced skin inflammation by reducing dermatitis scores, mast cell infiltration, skin structural damage, and serum inflammatory mediator levels. Additionally, DCQA and ABL significantly inhibited JAK/STAT activation in interferon-γ/TNF-α-treated keratinocytes. Furthermore, ligand-binding analysis revealed high binding affinities of DCQA and ABL for JAK. These results suggest the pharmacological potential of WEIF to alleviate DfE-induced skin inflammation by inhibiting the JAK/STAT signaling pathway. In conclusion, these findings support the development of WEIF as a therapeutic treatment for AD-like skin inflammatory diseases. Full article

TREM2 (triggering receptor expressed on myeloid cells 2) is a membrane-bound receptor primarily expressed on microglia in the central nervous system (CNS). TREM2 plays a crucial role in regulating immune responses, phagocytosis, lipid metabolism, and inflammation. Mutations in the TREM2 gene have been linked to various neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and Nasu–Hakola disease (NHD). These mutations are suggested to impair microglial activation and reduce the ability to clear amyloid aggregates, leading to exacerbated neuroinflammatory responses and accelerating disease progression. This review provides an overview of TREM2 structure, functions, and known pathogenic variants—including Arg47His, Arg62His, His157Tyr, Tyr38Cys, and Thr66Met. Furthermore, the molecular and cellular consequences of TREM2 mutations are introduced, such as impaired ligand binding, altered protein folding and trafficking, enhanced TREM2 shedding, and dysregulated inflammatory signaling. We also highlight recent advances in therapeutic strategies aimed at modulating TREM2 signaling. These include monoclonal antibodies (e.g., AL002, CGX101), small molecule agonists, and gene/cell-based therapies that seek to restore microglial homeostasis, enhance phagocytosis, and reduce neuroinflammation. While these approaches show promise in in vivo/in vitro studies, their clinical translation may be challenged by disease heterogeneity and mutation-specific responses. Additionally, determining the appropriate timing and precise dosing will be essential. Full article

Background: The amylin receptor is a receptor for the peptide hormone amylin, and its activation is known to reduce body weight. The amylin receptor functions as a heterodimer complex that consists of the calcitonin receptor for peptide hormone calcitonin and an accessary protein. Although the structural information of amylin receptors is currently available, receptor–ligand binding studies that support the peptide binding mode for amylin receptors remain incomplete. Methods: Here, we introduced mutagenesis to the amylin receptor 1 extracellular domain and examined mutational effects on peptide binding affinity. We focused on several residues mainly from the peptide-binding pocket (D97, D101, E123, N124, and N135 of the calcitonin receptor). Two well-known peptide ligands for amylin receptors were used for this study: a salmon calcitonin fragment and an antagonist amylin analog AC413 fragment with Y25P mutation. Results: Among the introduced mutations, D101A and N135A mutations abolished peptide ligand binding, suggesting that these residues are critical for peptide interaction. The N124A mutation also significantly decreased the peptide binding affinity by more than 8-fold. Intriguingly, the N124D mutation restored the decreased affinity of the salmon calcitonin fragment, while it failed to restore the decreased affinity of the AC413 fragment. Structural analyses suggested that there was a potential role of salmon calcitonin serine 29 in the interaction with aspartate of the N124D mutation. Conclusions: This study validates the critical residues of the amylin receptor 1 extracellular domain for the interaction with C-terminal fragments of peptide ligands. This study also suggests that modulating receptor–ligand interaction is feasible by the modification of receptor amino acids near an interacting peptide ligand. Full article

Holothuria scabra has long been acknowledged in traditional medicine for its therapeutic properties. The transforming growth factor-beta (TGF-β) superfamily is crucial in regulating cellular processes, including differentiation, proliferation, and immune responses. This study marks the first exploration of the gene expression localization, sequence conservation, and functional roles of H. scabra TGF-β proteins, specifically activin (HolscActivin), inhibin (HolscInhibin), and the TGF-β receptor (HolscTGFBR), across various organs. In situ hybridization indicated that HolscActivin and HolscInhibin are expressed in the intestine, respiratory tree, ovary, testis, and inner body wall. This suggests their roles in nutrient absorption, gas exchange, reproduction, and extracellular matrix remodeling. Notably, HolscTGFBR demonstrated a similar tissue-specific expression pattern, except for its absence in the respiratory tree. Bioinformatics analysis reveals that HolscTGFBR shares significant sequence similarity with HomsaTGFBR, especially in regions essential for signal transduction and inhibition. Molecular docking results indicate that HolscActivin may promote receptor activation, while HolscInhibin functions as a natural antagonist, reflecting the signaling mechanisms of human TGF-β proteins. Interestingly, cross-species ternary complex docking with human TGF-β receptors further supports these findings, showing that HolscActivin moderately engages the receptors, whereas HolscInhibin exhibits strong binding, suggestive of competitive inhibition. These results indicate that H. scabra TGF-β proteins retain the structural and functional features of vertebrate TGF-β ligands, supporting their potential applications as natural modulators in therapeutic and functional food development. Full article

Cell adhesion molecules (CAMs) are cell-surface-localized proteins mediating interactions of cells with other cells and the extracellular matrix. CAMs influence cell behavior and survival by inducing various intracellular signaling cascades that regulate diverse cellular processes including cytoskeleton remodeling and gene expression. Here, we review the evidence demonstrating that the levels, subcellular distribution, and binding affinities of CAMs of several major families including integrins, cadherins, immunoglobulin superfamily, and selectins are regulated by intracellularly generated or extracellular reactive oxygen species (ROS). Remarkably, CAMs themselves induce ROS production in response to binding to their ligands by activating lipoxygenases or NADPH oxidases or influencing ROS generation in mitochondria. CAM-dependent ROS production is essential for CAM-mediated cell adhesion and CAM-dependent intracellular signaling. Importantly, CAMs also protect cells from the ROS-induced cell death by stimulating the synthesis of antioxidants and suppressing the cell death signaling. A better understanding of the role ROS play in controlling CAM functions and mechanisms of this control may pave the way to modulating the functions of CAMs in various disorders associated with abnormal cell adhesion. Full article

Coumarins are known for interacting with proteins and exhibiting diverse biological activities. This study investigates the interaction between coumarin-343 (C343) and human (HSA) and bovine (BSA) serum albumins. Fluorescence spectroscopy and theoretical simulations, including density functional theory (DFT) and molecular docking, were used to analyze the ligand–protein complex formation. The fluorescence quenching data revealed that C343 binds to both proteins, with binding constants of 2.1 × 10⁵ mol·L⁻¹ (HSA) and 6.5 × 10⁵ mol·L⁻¹ (BSA), following a 1:1 stoichiometry. Binding site markers identified drug site I (DS1), located in subdomain IIA, as the preferential binding region for both proteins. Computational results supported these findings, showing high affinity for DS1, with binding energies of −69.02 kcal·mol⁻¹ (HSA) and −67.22 kcal·mol⁻¹ (BSA). While complex formation was confirmed for both proteins, differences emerged in the induced circular dichroism (ICD) signals. HSA displayed a distinct ICD profile compared to BSA in both intensity and absorption maximum. Molecular Docking revealed that the C343 conformation differed between HSA and BSA, explaining the variation in ICD signals. These results highlight the importance of protein structure in modulating ligand interactions and spectral responses. Full article

The design of small-molecule inhibitors targeting proprotein convertase subtilisin/Kein type 9 (PCSK9) remains a forefront challenge in combating atherosclerosis. While various monoclonal antibodies have achieved clinical success, small-molecule inhibitors are hindered by the unique structural features of the PCSK9 binding interface. In this study, a potential small-molecule inhibitor was identified through virtual screening, followed by molecular dynamics (MD) simulations to explore the binding mechanisms between the inhibitor and the PCSK9 protein. Binding free energies were calculated using molecular mechanics/Generalized Born surface area (MM/GBSA) with the interaction entropy (IE) method, and critical hot-spot residues were identified via alanine scanning analysis. Key residues, including ARG237, ILE369, ARG194 and PHE379, were revealed to form critical interactions with inhibitor and play dominant roles during the inhibitor’s binding. In addition, the polarization effect was shown to significantly influence PCSK9–ligand binding. The identified inhibitor exhibited highly similar binding patterns with two known active compounds, providing valuable insights for the rational design and optimization of small-molecule inhibitors targeting PCSK9. This work contributes to the development of more effective treatments for hyperlipidemia and associated cardiovascular diseases. Full article

(1) Background: The highly pathogenic avian influenza virus H5N1 clade 2.3.4.4b is an emerging threat that poses a great risk to the poultry industry. A few human cases have been linked to the infection with this clade in many parts of the world, including the USA. Unfortunately, there are no specific vaccines or antiviral drugs that could help prevent and treat the infection caused by this virus in birds. Our major objective is to identify/repurpose some (novel/known) antiviral compounds that may inhibit viral replication by targeting some key viral proteins. (2) Methods: We used state-of-the-art machine learning tools such as molecular docking and MD-simulation methods from Biovia Discovery Studio (v24.1.0.321712). The key target proteins such as hemagglutinin (HA), neuraminidase (NA), Matrix-2 protein (M2), and the cap-binding domain of PB2 (PB2/CBD) homology models were validated through structural assessment via DOPE scores, Ramachandran plots, and Verify-3D metrics, ensuring reliable structural representations, confirming their reliability for subsequent in silico approaches. These approaches include molecular docking followed by molecular dynamics simulation for 50 nanoseconds (ns), highlighting the structural stability and compactness of the docked complexes. (3) Results: Molecular docking revealed strong binding affinities for both sofosbuvir and GS441524, particularly with the NA and PB2/CBD protein targets. Among them, GS441524 exhibited superior interaction scores and a greater number of hydrogen bonds with key functional residues of NA and PB2/CBD. The MM-GBSA binding free energy calculations further supported these findings, as GS441524 displayed more favorable binding energies compared to several known standard inhibitors, including F0045S for HA, Zanamivir for NA, Rimantadine and Amantadine for M2, and PB2-39 for PB2/CBD. Additionally, 50 ns molecular dynamics simulations highlighted the structural stability and compactness of the GS441524-PB2/CBD complex, further supporting its potential as a promising antiviral candidate. Furthermore, hydrogen bond monitor analysis over the 50 ns simulation confirmed persistent and specific interactions between the ligand and proteins, suggesting that GS441524 may effectively inhibit the NA, and PB2/CBD might potentially disrupt PB2-mediated RNA synthesis. (4) Conclusions: Our findings are consistent with previous evidence supporting the antiviral activity of certain nucleoside analog inhibitors, including GS441524, against various coronaviruses. These results further support the potential repurposing of GS441524 as a promising therapeutic candidate against H5N1 avian influenza clade 2.3.4.4b. However, further functional studies are required to validate these in silico predictions and support the inhibitory action of GS441524 against the targeted proteins of H5N1, specifically clade 2.3.4.4b. Full article

Human Interleukin-6 (hIL-6) is a pro inflammatory cytokine that binds to its receptor, IL-6Rα followed by binding to gp130 and subsequent dimerization to form a hexamer signaling complex. As a critical inflammation mediator, hIL-6 is associated with a diverse range of diseases and monoclonal antibodies in clinical use that either target IL-6Rα or hIL-6 to inhibit signaling. Here, we perform high-throughput structure-based computational screening using ensemble docking for small-molecule antagonists for which the target conformations were taken from 600 ns long molecular dynamics simulations of the apo protein. Prior knowledge of the contact sites from binary complex studies and experimental work was incorporated into the docking studies. The top 20 scoring ligands from the in silico studies after post analysis were subjected to in vitro functional assays. Among these compounds, the ligand with the second-highest calculated binding affinity experimentally showed an ~84% inhibitory effect on IL6-induced STAT3 reporter activity at 10 μM concentration. This finding may pave the way for designing small-molecule inhibitors of hIL-6 of therapeutic significance. Full article

G-protein-coupled receptors (GPCRs) are vital transmembrane proteins that regulate a wide range of physiological processes by transmitting extracellular signals into intracellular responses. Among them, the β2-adrenergic receptor (β2-AR) plays a central role in bronchodilation, smooth muscle relaxation, and cardiovascular modulation, making it a key therapeutic target for diseases such as asthma, chronic obstructive pulmonary disease (COPD), and hypertension. This study explores the potential of natural bioactive compounds like ephedrine, quercetin, catechin, and resveratrol as alternative ligands for β2-AR through molecular docking analysis. Using AutoDock 4.6, these compounds were docked with the binding site of the β2-AR (PDB ID: 2RH1), and their binding affinities and interaction map were evaluated. Results showed that all compounds exhibited favorable binding energies and stable interactions with key receptor residues, with quercetin demonstrating the highest affinity. The findings suggest that these natural compounds may serve as promising leads for the development of safer, plant-derived modulators of β2-AR, supporting the role of computational approaches in natural product-based drug discovery. However, as docking cannot determine functional activity, these findings should be interpreted as preliminary and require experimental validation. Full article

Antioxidants derived from plant extracts have attracted considerable attention due to their potential in mitigating oxidative damage through free radical scavenging mechanisms. Although 700 species have been used for centuries in Georgian traditional medicine, the chemical composition and antioxidant and antibacterial properties of Caucasian endemic medicinal plants remain largely unknown. In this study, the antioxidant and antibacterial activities of leaf and root extracts of Caucasian endemic medicinal plants Sempervivum transcaucasicum Muirhead and Paeonia daurica subsp. mlokosewitschii (Lomakin) D. Y. Hong were investigated. The highest antioxidant activity and phenolic and flavonoid content were revealed in Paeonia daurica leaf extract. The analysis of the content of water-soluble antioxidants revealed the highest content of reduced glutathione and ascorbate in Paeonia daurica leaves. Moreover, the antibacterial activity of leaf and root extracts against Escherichia coli ATCC 25922 strain was investigated, and minimal inhibitory concentration (MIC) values were determined. While the antibacterial activity against E. coli ATCC 25922 was not revealed for the Sempervivum transcaucasicum leaf extract, antibacterial properties were detected for the root extract (MIC 5 mg/mL). Collectively, the highest antibacterial activity was revealed for Paeonia daurica leaf and root extracts (MIC 2 mg/mL and 3 mg/mL, respectively). From a molecular perspective, molecular docking simulations were performed using HDOCK software, with reduced glutathione and ascorbic acid as ligands, in order to analyse their potential binding affinity to the OmpX protein. Inhibiting this protein would likely disrupt bacterial function and produce an antibacterial effect. Our results provide a possible mechanism for the antibacterial activity of Paeonia daurica subsp. mlokosewitschii. Overall, the results of the study demonstrate the potential of Caucasian endemic medicinal plants as natural antioxidants and antimicrobial agents. Full article

Background/Objectives: Severe malaria, mainly caused by Plasmodium falciparum, remains a significant therapeutic challenge due to increasing drug resistance and adverse effects. Flavonoids, known for their wide range of bioactivities, offer a promising route for antimalarial drug discovery. The aim of this study was to elucidate key structural features associated with antimalarial activity in flavonoids and to develop accurate, interpretable predictive models. Methods: Curated databases of flavonoid structures and their activity against P. falciparum strains and enzymes were constructed. Molecular fingerprinting and decision tree analyses were used to identify key pharmacophoric groups. Subsequently, molecular descriptors were generated and reduced to build multiple classification and regression models. Results: These models demonstrated high predictive accuracy, with test set accuracies ranging from 92.85% to 100%, and R² values from 0.64 to 0.97. Virtual screening identified novel flavonoid candidates with potential inhibitory activity. These were further evaluated using molecular docking and molecular dynamics simulations to assess binding affinity and stability with Plasmodium proteins (FabG, FabZ, and FabI). The predicted active ligands exhibited stable pharmacophore interactions with key protein residues, providing insights into binding mechanisms. Conclusions: This study provides highly predictive models for antimalarial flavonoids and enhances the understanding of structure–activity relationships, offering a strong foundation for further experimental validation. Full article