Search Results (289)

Antibiotic-resistant infections remain a major challenge in cystic fibrosis (CF), where chronic Pseudomonas aeruginosa colonization drives lung infection. The overexpression of adhesion-related proteins and extracellular matrix components, including fibronectin (Fn), facilitates bacterial colonization. Recent evidence identifies the RNA-binding protein Human Antigen R (HuR) as a key regulator of this process, as it stabilizes Vav3 mRNA, promoting Fn deposition and the formation of bacterial docking platforms. Here, we report the synthesis, optimization, and functional evaluation of the HuR-targeted small-molecule (2S,3S)-BOPC1. Functional assays in CF human airway epithelial cells demonstrated that (2S,3S)-BOPC1 significantly reduced P. aeruginosa adhesion in a dose-dependent manner without detectable cytotoxic effects. These findings provide the first evidence that targeting HuR can disrupt the HuR–Vav3–Fn axis, reducing bacterial attachment. This host-directed approach represents a promising strategy to prevent chronic infections in CF without promoting antibiotic resistance. Full article

The increasing threat of zoonotic malaria parasites of humans, such as Plasmodium knowlesi, make the search for improved pharmacotherapy imperative. Using protein sequence and structural analyses, phylogenetics, protein network mapping, protein–ligand interaction, and small molecule docking studies, we have identified for the first time the predicted structure, function, and druggability of the P. knowlesi heat shock protein 90s (PkHsp90s). Four isoforms were identified (in the cytosol, endoplasmic reticulum, mitochondrion, and apicoplast), and key structural differences were elucidated compared to human Hsp90s. In particular, the glycine-rich helix loop (GHL) motif of cytosolic PkHsp90 was predicted to have a straight conformation that forms a plasmodial-specific hydrophobic extension of the lid domain of the ATP-binding site, which was not observed for the cytosolic human Hsp90s, HSPC1 (Hsp90α), and HSPC3 (Hsp90β). Virtual screening identified for the first time a number of compounds from the ZINC database (ZINC22007970, ZINC724661072, and ZINC724661078) that were predicted to bind strongly to the GHL-associated pocket of PkHsp90, with weak or no binding to HSPC1. This study has provided a molecular framework in support of rational drug design, targeting PkHsp90s as a promising route for antimalarial drug development in the fight against zoonotic malaria. Full article

Background: Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide and is associated with a poor prognosis. Oxidative stress is a key factor in the occurrence and progression of HCC. KHK-A, a key protein in the oxidative stress pathway, plays an important role in various cancers. This study aimed to discover small-molecule inhibitors targeting KHK-A through structure-based virtual screening, evaluate their therapeutic effects on HCC, and explore the potential of KHK-A as a therapeutic target for HCC. Methods: Based on the crystal structure of KHK-A, potential small-molecule inhibitors (HK1 to HK-24) were screened from the SPECS database using the Discovery Studio (DS) 2019 software. The effects of these compounds were evaluated through molecular docking and cellular experiments. Results: The screened compound HK-4 significantly inhibited HCC cell proliferation, migration, and invasion ex vivo. The half-maximal inhibitory concentrations (IC₅₀) of HK-4 in HepG2, PLC/PRF/5, and HuH7 cells were 22.54 µM, 23.91 µM, and 23.38 µM, respectively. HK-4 induced G1 phase arrest and apoptosis, and reduced the protein levels of p-AKT and p-mTOR in the PI3K-AKT signaling pathway. Conclusions: Through structure-based virtual screening, this study identified HK-4, a small-molecule inhibitor of KHK-A with anti-HCC activity. Its mechanism of action is closely related to the regulation of the PI3K-AKT signaling pathway. This finding provides experimental evidence supporting KHK-A as a therapeutic target for HCC and offers a new direction for the development of novel anti-HCC drugs. Full article

Curcumin is a widely researched natural molecule due to its abundance of pharmacological effects, such as antioxidant, antitumor, anti-inflammatory, etc. The main limitation of curcumin, however, is its low aqueous solubility, which worsens its biopharmaceutical characteristics. The aim of this study was to encapsulate curcumin in albumin nanoparticles and to subsequently incorporate them into a polyvinyl alcohol patch, resulting in a new drug formulation for skin application. The nanoparticles were characterized by a small mean diameter of approximately 162 nm, a narrow size distribution, and a negative zeta potential. TEM confirmed the small size of the nanoparticles. The ratio between the drug and albumin was optimized, achieving approximately 88% encapsulation efficiency. Protein–ligand docking, utilizing CB-Dock, indicated a strong interaction between curcumin and albumin. The binding between the molecules was proved via diffuse-reflectance UV–vis and XRD analyses. The encapsulated curcumin showed a significantly potentiated scavenging activity against ABTS and DPPH radicals in comparison with the pure drug, as well as a protective effect in H₂O₂-induced oxidative stress in fibroblasts. The loaded nanoparticles were further incorporated in a PVA hydrogel patch, which was characterized in terms of mechanical properties and in vitro release. Therefore, the resulting system could provide more effective skin delivery and an improved antioxidant activity of curcumin. Full article

Background: Multidrug resistance (MDR) remains a major obstacle in cancer chemotherapy, and overexpression of ABCB1 plays a critical role in the pathogenesis of MDR. Despite decades of research, significant clinical progress in the development of ABCB1 inhibitors has yet to be achieved. The small-molecule H89 is originally identified as an inhibitor of protein kinase A (PKA), but it also exhibits various functions unrelated to the PKA. This study investigates H89 as a novel ABCB1-inhibitor to reverse MDR in colorectal cancer (CRC). Methods: Cytotoxicity assays were performed on ABCB1-overexpressing MDR cell line HCT-8/V and parental CRC cell line HCT-8. Drug accumulation was quantified via flow cytometry, and cell cycle effects were analyzed using propidium iodide staining. The ATPase activity of ABCB1 was detected using an ATPase activity assay kit. Molecular docking utilized the ABCB1 crystal structure. Results: Both 3 μM and 10 μM H89 significantly reverses resistance to two ABCB1 substrate drugs (doxorubicin and vincristine) in HCT-8/V cells in a dose-dependent manner, with no such effect observed inHCT-8 cells. The combination of H89 and doxorubicin or vincristine resulted in a significant increase in the proportion ofHCT-8/Vcells in the sub-G1 and G2/M phases. Further mechanistic studies reveal that H89 exerts its effect by inhibiting the drug efflux function of ABCB1, thereby increasing the intracellular accumulation of the substrate drugs and reversing multidrug resistance. Furthermore, H89 did not alter the expression of ABCB1. H89 effectively inhibited the ATPase activity of ABCB1. Molecular docking simulations revealed the binding mode of H89 with ABCB1. Conclusions: The combination of H89 with ABCB1 substrate drugs significantly reverses multidrug resistance in colorectal cancer. These findings provide a strong theoretical and experimental foundation for the development of novel MDR-reversing agents targeting ABCB1. Full article

Blind docking predicts binding interactions between two molecular entities without prior knowledge of the binding site. This approach is essential because it explores the entire surface of the receptor to identify potential interaction sites. Blind docking widely works for both protein–protein and ligand–protein interaction studies. In protein–protein blind docking, the method aims to predict the correct orientation and interface of two proteins forming a complex. Protein blind docking is particularly valuable in studying transient interactions, protein–protein recognition, signaling pathways, tentative and significant biomolecular assemblies where structural data is limited. Ligand–protein blind docking discovers potential binding pockets across the entire protein surface. It is frequently applied in early-stage drug discovery, especially for novel or poorly characterized targets. The method helps identify allosteric sites or novel binding regions that are not evident from known structures. Overall, blind docking provides a versatile and powerful tool for studying molecular interactions, enabling discovery even in the absence of detailed structural information. In this scenario, we reported a timeline of attempts to improve this kind of computational approach with ML and hybrid approaches to obtain more reliable predictions. We dedicate two main sections to protein–protein and protein-ligand blind docking, presenting the reliability and caveats for each approach and outlining potential future directions. Full article

CRISPR-Cas systems have transformed genome engineering with their exceptional precision, programmability, and affordability. Although they originate from microbial defense mechanisms, expanding their use, especially in therapeutics, requires a chemically oriented framework that allows for tunable, reversible, and safe gene editing. This review offers a multidisciplinary look at recent progress in the structural, synthetic, and computational aspects of CRISPR-Cas technologies. Structural analyses examine the domain architectures of Cas enzymes, including the recognition (REC), nuclease (HNH and RuvC), and PAM-interacting domains, emphasizing the catalytic importance of divalent metal ions. Comparative insights into Cas9, Cas12, and Cas13 demonstrate functional diversity across DNA- and RNA-targeting systems, supported by high-resolution structural data on guide RNA pairing and conformational dynamics. The review highlights advances in chemical modulation, such as anti-CRISPR proteins, small-molecule inhibitors, and stimuli-responsive switches, focusing on structure–activity relationships. Additionally, bioorganic delivery systems like lipid nanoparticles, polymers, and cell-penetrating peptides are discussed for their role in improving in vivo delivery through formulation chemistry. Computational chemistry methods—molecular docking, molecular dynamics simulations, and virtual screening—are identified as critical tools for discovering and optimizing modulators. The use of AI-driven tools is proposed as a promising direction for rational CRISPR design. Overall, this chemistry-focused perspective emphasizes the importance of molecular control in developing the next generation of programmable and safe CRISPR-based therapies. Full article

The Aurora kinase A (Aurora-A), overexpressed in cancer cells, represents a promising anti-cancer therapeutic target due to its role in mitotic progression and chromosome instability. Aurora-A contains a recently described drug pocket within its Targeting Protein for Xklp2 (TPX2) interaction site, offering a promising target for small-molecule disruption and selective inhibition. In this study, 1281 natural products from Argentina’s database (NaturAr), encompassing chemically diverse and structurally rich metabolites, were evaluated using a machine learning model based on molecular fingerprints and variational autoencoders (VAEs) to predict inhibitory activity with high-throughput efficiency. From this initial screening, 624 compounds were classified as active type against Aurora-A, and subsequently subjected to molecular docking using FRED software (v4.3.0.3) against the Aurora-A crystal structure (PDB: 5OSD), focusing on the TPX2-binding interface. Among them, 117 compounds with various scaffolds showed better binding scores than the co-crystallized ligand, highlighting their potential to interact with the druggable target site through stable and specific molecular contacts. This workflow effectively prioritized compounds of natural origin from Argentina for the discovery of new Aurora-A kinase inhibitors, demonstrating the value of integrating AI-driven screening with structure-based modeling. These findings highlight the identification of novel scaffolds with high binding potential, offering promising starting points for the development of selective Aurora-A inhibitors. Full article

Zika virus (ZIKV) caused Zika outbreaks and continues to post threats to public health. ZIKV infection may cause congenital abnormalities during pregnancy and neurological manifestations in adults. The recurrent public health threat of Zika in various geographical areas demonstrates a need for the development of effective therapeutics. Currently, there are no approved therapies for Zika. ZIKV is a single-stranded, positive-sense RNA virus, whose genome encodes three structural proteins and seven non-structural proteins. The surface envelope (E) protein is essential for host–cell recognition and viral entry; therefore, inhibition of E-mediated viral entry is a key strategy underlying antiviral treatments. Here, molecular docking-based virtual screening was used to screen small-molecule compound libraries to identify potential ZIKV entry inhibitors. Among the compounds identified, Pyrimidine-Der1 exhibited efficient inhibition of reporter ZIKV infection. The microscale thermophoresis assay confirmed its binding with the ZIKV E protein. This compound has effective inhibition of authentic ZIKV infection in a plaque inhibition assay against R103451, PAN2016, and FLR human strains (IC₅₀: ~3–5 μM). Additionally, it efficiently inhibited ZIKV infection at viral entry and fusion steps of the virus life cycle in a time-of-addition assay. Overall, Pyrimidine-Der1 is a promising ZIKV entry inhibitor, warranting further optimization and evaluation. Full article

Nanoplastics are pervasive contaminants that adversely affect male reproductive function, yet the molecular basis of polystyrene nanoplastic (PS-NP) toxicity in immature testes and effective preventive strategies remain unclear. Here, male mice (postnatal days 22–35, PND 22–35) and TM3 Leydig cells were exposed to graded PS-NPs, followed by transcriptomic profiling to identify differentially expressed genes (DEGs). Candidate therapeutics were prioritized using Connectivity Map (CMap) analysis and molecular docking, and protein interactions were examined by co-immunoprecipitation (Co-IP). PS-NPs accumulated in immature testes, eliciting excessive reactive oxygen species (ROS) and activation of NF-κB. These events coincided with the downregulation of steroidogenic enzymes (CYP11A1 and StAR) and disruption of testicular microarchitecture. In TM3 cells, PS-NPs suppressed testosterone synthesis in a concentration-dependent manner; this effect was fully reversed by pretreatment with N-acetylcysteine (NAC) or Bay 11-7082. Co-IP demonstrated p65–steroidogenic factor-1 (SF-1) binding consistent with formation of a transcriptional repressor complex targeting steroidogenic genes. CMap and docking analyses nominated parthenolide (PTL) as a candidate inhibitor of NF-κB nuclear translocation (predicted binding affinity, −6.585 kcal/mol), and PTL mitigated PS-NP-induced impairment of testosterone synthesis in vitro. Collectively, these data indicate that PS-NPs disrupt testosterone biosynthesis in immature testes through the ROS/NF-κB/p65–SF-1 axis, while PTL emerges as a candidate small molecule to counter nanoplastic-associated reproductive toxicity. These findings underscore translational relevance and support future evaluation under chronic low-dose exposure conditions, including in vivo validation of PTL efficacy, pharmacokinetics, and safety. Full article

Background: The pathogenesis of Alzheimer’s disease (AD) is complex, and effective treatments remain elusive. Growing evidence suggests that dietary factors may play a significant role in preventing or alleviating AD. Bergapten (BG), a natural compound with anti-inflammatory properties, has been studied; however, its specific role in neuroinflammation and AD pathogenesis remains unclear. Methods: Through public databases and bioinformatics tools, the possible molecular mechanisms of BG’s effects on AD were analyzed. Six-month-old 5×FAD mice underwent intragastric administration of BG for 30 consecutive days. Learning and memory abilities were assessed using the novel object recognition (NOR) test and the Morris water maze (MWM) test. Immunofluorescence staining, Western blot and q-PCR was conducted to assess the underlying mechanisms. In vitro experiments used Aβ-stimulated BV2 microglial cells for BG intervention. Results: Bioinformatics analysis revealed the MAPK signaling pathway as the top-ranked pathway. Molecular docking studies further demonstrated strong binding interactions between BG and key proteins within the MAPK pathway. In behavioral studies, NOR test and MWM test demonstrated that BG treatment improved learning and memory abilities in 5×FAD mice. Additionally, BG treatment significantly reduced Aβ deposition, pro-inflammatory cytokine levels, and inhibited excessive microglial activation in these mice. Consistent with in vivo findings, BG effectively decreased pro-inflammatory cytokines in Aβ-stimulated BV2 microglial cells. Mechanistic studies revealed that BG attenuates neuroinflammatory responses by inhibiting the MAPK signaling pathway both in vivo and in vitro. Conclusions: Our findings suggest that BG mitigates AD pathological features by suppressing MAPK-mediated neuroinflammation and represents a promising natural small molecule for the prevention and treatment of AD. Full article

The accumulation of high levels of manganese ions complexed with small molecules has been proposed as a pivotal factor contributing to the extraordinary radiation resistance of Deinococcus radiodurans. However, the molecular mechanisms governing the manganese ion homeostasis remain elusive. In this study, we characterize the role of the MntABC transporter system for Mn ion accumulation in D. radiodurans. Its cellular membrane localization is unequivocally demonstrated through fluorescence labeling techniques. Mutation of the protein components of the MntABC led to a significant decrease in intracellular Mn ion accumulation, concomitant with impaired cellular growth, decreased resistance against hydrogen peroxide, and gamma-ray irradiation-induced oxidative stresses, indicating that the MntABC system plays an indispensable role in resistance of D. radiodurans to oxidative stresses. Protein structure modeling and molecular docking are employed to analyze the key active sites of the MntABC proteins and their intermolecular interactions. The results demonstrate that the MntABC system is essential for maintaining Mn ion homeostasis and the oxidative stress resistance of D. radiodurans. Full article

As a medicinal and edible homologous substance, ginkgo seeds’ historical application in headache management, documented from Diannan Materia Medica to contemporary clinical practice, is based on empirical evidence. This study employed network pharmacology and molecular docking to explore the anti-migraine mechanisms of ginkgo seeds. In total, 10 related signal pathways (cancer pathway, lipid and atherosclerosis, Phosphatidylinositol 3-Kinase–Protein Kinase B (PI3K-AKT) signaling pathway, etc.) and 10 hub genes were identified through Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and in the inprotein–protein interaction (PPI) network. Molecular docking results demonstrated that formononetin, stigmasterol, and beta-sitosterol in ginkgo seeds can interact with 10 core targets (average binding energy ≤ −3.17 kcal/mol). This study analyzed the related pathways and targets of ginkgo seeds in the treatment of migraines, as well as the docking test of small-molecule ligands and target protein receptors, which provides a reference with which to find and explore effective preventive health foods for migraines. Full article

In recent decades, there has been a significant increase in new lung cancer cases and deaths globally, especially in China, which hindered the extension of human life expectancy and severely threatened public health. Natural products are important and sustainable sources of new anticancer drug molecules, offering new bioactive molecules with various structures and biofunctions for new anticancer drug development, which accounted for 40% of all anticancer drugs. Natural-based compounds could inhibit cancer cell proliferation and migration through a variety of anticancer mechanisms by the modulation/regulation of multiple biotargets and cell signaling pathways. In this review, we summarized the anticancer activities of flavonoids, terpenoids, glycosides, alcohols, coumarins, saccharides, and other natural compounds that could modulate the ERK-related signaling pathway in non-small-cell lung cancer (NSCLC) cells. We further elucidated the mechanistic pathways of natural compound combinations and computationally predicted their molecular docking affinities with ERK1/ERK2 protein targets, as well as providing an outlook on current studies, with the expectation that natural compounds will play more significant roles in future antitumor chemotherapy regimens. Full article

Background: Cardiomyocyte death is a key factor in myocardial ischemia–reperfusion injury (MI/RI), and the expression patterns and molecular mechanisms of pyroptosis-related genes (PRGs) in ischemia–reperfusion injury are poorly understood. Methods: The mouse MI/RI injury-related datasets GSE61592 and GSE160516 were obtained from the Gene Expression Omnibus database, and differential expression analysis was performed on each to identify differentially expressed genes (DEGs). The DEGs were intersected with the PRGs obtained from GeneCards to identify differentially expressed PRGs in MI/RI. Enrichment analysis identified key pathways, while PPI network analysis revealed hub genes. The expression patterns and immune cell infiltration of hub genes were also investigated. The molecular docking prediction of key genes was performed using MOE software in conjunction with the ZINC small molecular compounds database. Key gene expression was validated in an external dataset (GSE4105), a mouse MI/RI model, and an HL-1 cell hypoxia/reoxygenation model via RT-qPCR. Results: A total of 29 differentially expressed PRGs were identified, which are primarily associated with pathways such as “immune system process”, “response to stress”, “identical protein binding”, and “extracellular region”. Seven key genes (Fkbp10, Apoe, Col1a2, Ppic, Tlr2, Fstl1, Serpinh1) were screened, all strongly correlated with immune infiltration. Seven FDA-approved small molecule compounds exhibiting the highest docking potential with each key gene were selected based on a comprehensive evaluation of S-scores and hydrogen bond binding energies. Apoe, Tlr2, and Serpinh1 were successfully validated across external datasets, the mouse MI/RI model, and the cardiomyocyte H/R model. Conclusions: Apoe, Tlr2, and Serpinh1 may be key genes involved in MI/RI-related pyroptosis. Targeting these genes may provide new insights into the treatment of MI/RI. Full article