Search Results (283)

Background/Objectives: Cancer progression is characterized by the suppression of apoptosis, activation of metastatic processes, and dysregulation of cell proliferation. The proper functioning of these mechanisms relies on critical signaling pathways, including Phosphoinositide 3-kinase/Protein kinase B/mammalian Target of Rapamycin (PI3K/Akt/mTOR), Mitogen-Activated Protein Kinase (MAPK), and Signal Transducer and Activator of Transcription 3 (STAT3). Although curcumin and resveratrol exhibit anticancer properties and affect these pathways, their pharmacokinetic limitations, including poor bioavailability and low solubility, restrict their clinical application. The aim of our study was to evaluate the synergistic anticancer potential of curcumin and resveratrol through hybrid molecules rationally designed from these compounds to mitigate their pharmacokinetic limitations. Furthermore, we analyzed the multi-target anticancer effects of these hybrids on the AKT serine/threonine kinase 1 (AKT1), MAPK, and STAT3 pathways using in silico molecular modeling approaches. Methods: Three hybrid molecules, including a long-chain (ELRC-LC) and a short-chain (ELRC-SC) hybrid, an ester-linked hybrid, and an ether-linked hybrid (EtLRC), were designed using the Avogadro software (v1.2.0), and their geometry optimization was carried out using Density Functional Theory (DFT). The electronic properties of the structures were characterized through Frontier Molecular Orbital (FMO), Molecular Electrostatic Potential (MEP), and Fourier Transform Infrared (FTIR) analyses. The binding energies of the hybrid molecules, curcumin, resveratrol, their analogs, and the reference inhibitor were calculated against the AKT1, MAPK, and STAT3 receptors using molecular docking. The stabilities of the best-fitting complexes were evaluated through 100 ns molecular dynamics (MD) simulations, and their binding free energies were estimated using the Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) method. Results: DFT analyses demonstrated stable electronic characteristics for the hybrids. Molecular docking analyses revealed that the hybrids exhibited stronger binding compared to curcumin and resveratrol. The binding energy of −11.4 kcal/mol obtained for the ELRC-LC hybrid against AKT1 was particularly remarkable. Analysis of 100 ns MD simulations confirmed the conformational stability of the hybrids. Conclusions: Hybrid molecules have been shown to exert multi-target mechanisms of action on the AKT1, MAPK, and STAT3 pathways, and to represent potential anticancer candidates capable of overcoming pharmacokinetic limitations. Our in silico-based study provides data that will guide future in vitro and in vivo studies. These rationally designed hybrid molecules, owing to their receptor affinity, may serve as de novo hybrid inhibitors. Full article

RNA polymerases are essential enzymes that catalyze DNA transcription into RNA, vital for protein synthesis, gene expression regulation, and cellular responses. Non-template-dependent RNA polymerases, which synthesize RNA without a template, are valuable in biological research due to their flexibility in producing RNA without predefined sequences. However, their substrate polymerization mechanisms are not well understood. This study examines Poly (A) polymerase (PAP), a nucleotide transferase superfamily member, to explore its substrate selectivity using computational methods. Previous research shows PAP’s polymerization efficiency for nucleoside triphosphates (NTPs) ranks ATP > GTP > CTP > UTP, though the reasons remain unclear. Using 500 ns Gaussian accelerated molecular dynamics simulations, stability analysis, secondary structure analysis, MM-PBSA calculations, and Markov state modeling, we investigate PAP’s differential polymerization efficiencies. Results show that ATP binding enhances PAP’s structural flexibility and increases solvent-accessible surface area, likely strengthening protein–substrate or protein–solvent interactions and affinity. In contrast, polymerization of other NTPs leads to a more open conformation of PAP’s two domains, facilitating substrate dissociation from the active site. Additionally, ATP binding induces a conformational shift in residues 225–230 of the active site from a loop to an α-helix, enhancing regional rigidity and protein stability. Both ATP and GTP form additional π–π stacking interactions with PAP, further stabilizing the protein structure. This theoretical study of PAP polymerase’s substrate selectivity mechanisms aims to clarify the molecular basis of substrate recognition and selectivity in its catalytic reactions. These findings offer valuable insights for the targeted engineering and optimization of polymerases and provide robust theoretical support for developing novel polymerases for applications in drug discovery and related fields. Full article

Transketolase-like protein 1 (TKTL-1) has been implicated in altered cancer metabolism, yet its structure and molecular function remain poorly understood. In this study, we established a homology model of TKTL-1 using multiple templates and validated it through sequence alignment and structural comparison with the canonical transketolase (TKT). Binding-site identification was performed using CASTp, receptor cavity mapping, and blind docking, all of which consistently pointed to a conserved region involving interactive residues shared between TKT and TKTL-1. Comparative docking revealed the reduced affinity of TKTL-1 for TDP, supporting functional divergence between TKTL-1 and TKT. We further analyzed conserved residues and receptor surfaces, which enabled us to propose predictive scaffolds as potential modulators of TKTL-1. While these scaffolds remain theoretical, they provide a computational framework to guide future pharmacophore modeling, molecular dynamics simulations, and experimental validation. Together, our study highlights the structural features of TKTL-1, establishes its key differences from TKT, and lays the groundwork for future drug discovery efforts targeting cancer metabolism. Full article

Cid1 protein is a crucial component in the RNA interference pathway and abnormal nuclear RNA turnover processes, primarily responsible for adding uridine to the 3′ end of RNA. Cid1 exhibits selective polymerization of UTP over other nucleoside triphosphates. To explore the mechanism of this selectivity, five systems: free-Cid1, Cid1-ATP, Cid1-UTP, Cid1-CTP, and Cid1-GTP with 500 ns Gaussian accelerated molecular dynamics (GaMD) simulations were performed to investigate conformational changes and binding affinities between substrates and Cid1. The results showed that UTP formed stronger and more numerous non-covalent interactions with Cid1 compared to the other three substrates. The Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) binding energy analysis revealed a substrate preference for Cid1 polymerase in the order of UTP, followed by ATP, CTP, and GTP. These findings provide theoretical insights into the substrate selectivity mechanism of Cid1 and provide theoretical clues for the design and modification of Cid1 polymerase. Full article

Periodontitis is a common inflammatory disease affecting the supporting structures of teeth. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, is known for its therapeutic properties in various diseases, including periodontitis. This study aims to identify the gene targets of EGCG and investigate its potential in modulating molecular pathways associated with periodontitis. The potential gene targets of EGCG were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction databases, while genes associated with periodontitis were sourced from GeneCards and Gene Expression Omnibus (GEO) datasets. By overlapping the two datasets, ten common target genes were identified. To explore their functional relevance, enrichment analyses such as Gene Ontology (GO) and REACTOME pathway mapping were conducted. Protein–protein interaction (PPI) networks were then generated, and further analyses involving molecular docking and molecular dynamics (MD) simulations were carried out to evaluate the binding affinity and structural stability of EGCG with the selected target proteins. Ten common genes (MMP2, MMP14, BCL2, STAT1, HIF1A, MMP9, MMP13, VEGFA, ESR1, and PPARG) were identified. PPI network and GO and pathway analyses identified the promising hub genes as ESR1, MMP2, MMP9, MMP13, and STAT1 and which highlighted roles in tissue development, extracellular matrix remodeling, and signaling pathways such as interleukin and matrix metalloproteinase activities. Molecular docking and MD simulations revealed strong binding interactions between EGCG and key proteins (ESR1, MMP2, MMP9, MMP13, and STAT1), with favorable binding energies and stable complexes. Among these, ESR1 and MMP13 exhibited the most favorable docking scores and stability in molecular dynamics simulations and MM–PBSA calculations. This study provides valuable insights into the molecular mechanisms of EGCG in periodontitis treatment. The findings suggest that ESR1 and MMP13 are the most promising targets for EGCG, supported by strong binding interactions and stable conformations in simulations. These results offer a foundation for further experimental studies and potential therapeutic applications of EGCG in managing periodontitis. Full article

A series of twenty-five salicylic acid derivatives was synthesized and structurally characterized by ¹H and ¹³C-APT NMR and IR spectroscopic techniques, and HRMS analysis. The derivatives were subjected to biological evaluation against species of the genus Candida (C. albicans ATCC 90028, C. albicans CBS 5602, C. tropicalis CBS 94, and C. krusei CBS 573). In assays were used the broth microdilution method to determine the minimum inhibitory concentration (MIC) and verify the probable mechanism of action for antifungal activity. In the antifungal evaluation, compounds N-isobutyl-2-hidroxybenzamide (14), N-cyclohexyl-2-hydroxybenzamide (15), N-benzyl-2-hydroxybenzamide (16), N-4-methylbenzyl-2-hydroxybenzamide (17), N-4-methoxybenzyl-2-hydroxybenzamide (18), N-2,4-dimethoxybenzyl-2-hydroxybenzamide (19), N-4-fluorbenzyl-2-hiydroxybenzamide (22), and N-4-chlorobenzyl-2-hydroxybenzamide (23) were bioactive against at least one fungal strain. The compound with the best antifungal profile was N-cyclohexyl-2-hydroxybenzamide (15), which presented a MIC of 570.05 μM against most of the strains tested. The tests using ergosterol and sorbitol demonstrated that the compound does not act by altering cell wall functions or the plasmatic membrane in Candida species. The in silico analysis of 15 for antifungal activity in various biological targets suggested a probable multitarget mechanism. Therefore, the synthesis of salicylic acid derivatives resulted in compounds with a good antifungal profile. Full article

The mammalian target of rapamycin pathway, mTOR, is a crucial signaling pathway that regulates cell growth, proliferation, metabolism, and survival. Due to its dysregulation it is involved in several ailments such as cancer or age-related diseases. The discovery of mTOR and the understanding of its biological functions were greatly facilitated by the use of rapamycin, an antibiotic of natural origin, which allosterically inhibits mTORC1, effectively blocking its function. In this entirely computational study, we investigated mTOR’s interaction with seven ligands: two clinically established inhibitors (everolimus and rapamycin) and five lignin-derived oligomers, a renewable natural polyphenol recently used for the drug delivery of everolimus. The seven complexes were analyzed through all-atom molecular dynamics simulations in explicit solvent using a high-performance computing platform. Trajectory analyses revealed stable interactions between mTOR and all ligands, with lignin-derived compounds showing comparable or enhanced binding stability relative to reference drugs. To evaluate the stability of the molecular complex and the behavior of the ligand over time, we analyzed key parameters including root mean square deviation, root mean square fluctuation, number of hydrogen bonds, binding free energy, and conformational dynamics assessed through principal component analysis. Our results suggest that lignin fragments are a promising, sustainable scaffold for developing novel mTOR inhibitors. Full article

This study aimed to investigate the molecular binding mechanisms of bromocriptine toward histamine-associated targets, exploring both antagonist-like and other potential interaction modes that may support therapeutic repurposing. Network pharmacology was applied to identify histamine-related pathways and prioritize potential protein targets. CXCR4, GHSR, and OXTR were selected based on combined docking scores and pharmacophore modeling evidence. Molecular dynamics (MD) simulations over 100 ns assessed structural stability, flexibility, compactness, and solvent exposure. Binding site contact analysis and MM/PBSA free binding energy calculations were conducted to characterize binding energetics and interaction persistence. Bromocriptine exhibited stable binding to all three receptors, engaging key residues implicated in receptor modulation (e.g., Asp187 in CXCR4, Asp99 in GHSR, Arg232 in OXTR). The MM/PBSA ΔG_binding values of bromocriptine were −22.67 ± 3.70 kcal/mol (CXCR4 complex), −22.11 ± 3.55 kcal/mol (GHSR complex), and −21.43 ± 2.41 kcal/mol (OXTR complex), stronger than standard agonists and comparable to antagonists. Contact profiles revealed shared and unique binding patterns across targets, reflecting their potential for diverse modulatory effects. Bromocriptine demonstrates high-affinity binding to multiple histamine-associated GPCR targets, potentially exerting both inhibitory and modulatory actions. These findings provide a molecular basis for further experimental validation and therapeutic exploration in histamine-related conditions. Full article

Surfactants are used in various washing applications with potential negative environmental and health impacts. The ion-pair 1,3-dioctadecyl-1H-1,2,3-triazol-3-ium-tetraphenylborate (DODTA–TPB) was used to fabricate the potentiometric sensor for the quantification of anionic surfactants. The computational analysis of the DODTA⁺–TPB⁻ adduct reveals a dynamic, thermodynamically favorable interaction driven primarily by hydrophobic C–H∙∙∙π contacts and the flexibility of the C-18 chains, rather than electrostatic or π–π stacking forces. These findings, supported by the MM-PBSA, RDF, and structural analyses, align with broader trends in molecular recognition and provide a foundation for designing advanced ion-pair-based sensors. The sensor showed advanced analytical properties to anionic surfactants with low interfering effects of selected anions. The response of the SDS was investigated in the range from 8.1 × 10⁻⁸ M to 1.0 × 10⁻² M, with a slope of −59.2 mV and a limit of detection (LOD) of 3.1 × 10⁻⁷ M; and DBS was in the range of 8.1 × 10⁻⁸ M to 2.5 × 10⁻³ M with a slope of −57.5 mV and an LOD of 5.9 × 10⁻⁷ M. The sensor was tested on potential interfering ions. Potentiometric titrations of technical-grade anionic surfactants had high recovery rates from 100.2 to 100.4%. The recovery test for spiked samples of surface waters was from 94.2 to 96.5%. The sensor was tested on commercial samples containing anionic surfactants, and the results were compared and showed a good agreement with the two-phase titration method. Full article

Carbonic anhydrase IX (CA IX) is a transmembrane metalloenzyme that is increased in tumor cells under hypoxia and plays an important role in solid tumor acidification. It is a marker of tumor hypoxia and a prognostic factor in human malignancies. Given the critical role of CA IX and their over expression in many cancer tissues, they have emerged as a promising target for developing novel anticancer therapeutics. In this study we designed a pharmacophore model based on known inhibitors to screen small compound libraries to discover potential inhibitors of CA IX. Molecular docking experiments discovered that four compounds ZINC613262012, ZINC427910039, ZINC616453231, and DB00482 exhibited a strong binding affinity towards CA IX, mimicking the interaction pattern similar to native inhibitors. Molecular dynamics simulations and an MM-PBSA analysis revealed ZINC613262012, ZINC427910039, and DB00482 as the most potential and stable inhibitors with the binding free energies −10.92, −18.77, and −12.29 kcal/mol, respectively. In addition, DFT-based analyses supported their favorable electronic properties, further validating their potential as CA IX inhibitors. These three hits demonstrated a greater stability and compactness relative to the known inhibitors, suggesting these might be used CA IX inhibitors to treat tumors. Full article

Men have limited options for contraception, despite the widely accepted public health benefits of it, placing the contraceptive burden solely on women. The current study focuses on inhibiting the PP1γ2 enzyme, which plays a role in sperm maturation and motility. The study considered three top compounds based on the findings of molecular docking. The three compounds exhibited a good interaction profile with a binding affinity score of D751-0223 (−8.7 kcal/mol), D751-014 (−8.1 kcal/mol), and N117-0087 (−8 kcal/mol) measured in kcal/mol. Molecular dynamics simulation (MDS) were performed on the PP1γ2–ligand complexes along with the Apo form. The results suggested that all the complexes were stable with no major deviations observed compared to Apo. The average RMSDs for PP1γ2-D751-0223, D751-014, and Apo were 1.27 Å, 1.73 Å, 1.39 Å, and 1.69 Å, respectively. The PP1γ2–ligand complexes were observed with unique salt bridge interactions such as Glu133-Arg137, Asp4-Lys107, Asp188-Arg116, and Glu120-Arg90. The principal component analysis (PCA) findings indicated that every complex had a distinctive motion state. Furthermore, the net MM/PBSA scores for D751-0223, D751-0143, and N117-0087 were −80.01 kcal/mol, −72.18 kcal/mol, and −64.26 kcal/mol, respectively, while the MM/GBSA and MM/PBSA values were −82, −73.07,−67.26 and −80.01, −72.18, −64.26, measured in kcal/mol, respectively. The WaterSwap energy estimation was performed to validate the former technique, and the findings demonstrated that PP1γ2-D751-0223 is a stable complex, with a value of −51.05 kcal/mol. This work provides a baseline to researchers for the identification of novel therapeutic approaches for non-hormonal male contraceptives. Full article

Saffron (Crocus sativus L.) contains bioactive compounds with potential health benefits, including modulation of protein function and gene expression. However, their ability to tune the epigenetic machine remains poorly understood. This study employs molecular docking (AutoDock Vina 1.4), dynamics simulations, and MM/PBSA calculations to investigate the interactions between four saffron-derived molecules—crocetin, beta-D-glucosyl trans-crocetin, picrocrocin and safranal—and four epigenetic enzymes—DNMT1, DNMT3a, HDAC2, and SIRT1. Our in silico screening identifies beta-D-glucosyl trans-crocetin, one of the saffron’s crocins, as a potential DNMT1 inhibitor. Along with crocetin, it also shows the ability to inhibit HDAC2 and activate SIRT1. Picrocrocin displays a resveratrol-like ability to activate SIRT1. None of the saffron-derived compounds effectively bind or inhibit DNMT3a. Among the tested molecules, safranal shows no interaction with the selected epigenetic targets. These findings highlight saffron’s nutriepigenomic potential and emphasize the need for functional validation within relevant in vitro and in vivo experimental methodologies. Full article

Background: Hepatocellular carcinoma (HCC) is one of the most common and fatal malignancies worldwide, characterized by remarkable molecular heterogeneity and poor clinical outcomes. Despite advancements in diagnosis and treatment, the prognosis for HCC remains dismal, largely due to late-stage diagnosis and limited therapeutic efficacy. Therefore, there is a critical need to identify novel therapeutic targets and explore alternative strategies, such as drug repurposing, to improve patient outcomes. Methods: In this study, we employed network pharmacology, molecular docking, and molecular dynamics (MD) simulations to explore the potential therapeutic targets of Nirmatrelvir in HCC. Results: Nirmatrelvir targets were predicted through SwissTarget (101 targets), SuperPred (1111 targets), and Way2Drug (38 targets). Concurrently, HCC-associated genes (5726) were retrieved from DisGeNet. Cross-referencing the two datasets identified 29 overlapping proteins. A protein–protein interaction (PPI) network constructed from the overlapping proteins was analyzed using CytoHubba, identifying 10 hub genes, with HDAC1, HDAC3, and STAT3 achieving the highest degree scores. Molecular docking revealed a strong binding affinity of Nirmatrelvir to HDAC1 (docking score = −7.319 kcal/mol), HDAC3 (−6.026 kcal/mol), and STAT3 (−6.304 kcal/mol). Moreover, Nirmatrelvir displayed stable dynamic behavior in repeated 200 ns simulation analyses. Binding free energy calculations using MM/GBSA showed values of −23.692 kcal/mol for the HDAC1–Nirmatrelvir complex, −33.360 kcal/mol for HDAC3, and −21.167 kcal/mol for STAT3. MM/PBSA analysis yielded −17.987 kcal/mol for HDAC1, −27.767 kcal/mol for HDAC3, and −16.986 kcal/mol for STAT3. Conclusions: The findings demonstrate Nirmatrelvir’s strong binding affinity towards HDAC3, underscoring its potential for future drug development. Collectively, the data provide computational evidence for repurposing Nirmatrelvir as a multi-target inhibitor in HCC therapy, warranting in vitro and in vivo studies to confirm its clinical efficacy and safety and elucidate its mechanisms of action in HCC. Full article

Estrogen receptor alpha (ERα) plays a vital role in the development and progression of breast cancer by regulating the expression of genes associated with cell proliferation in breast tissue. ERα inhibition is a key strategy in the prevention and treatment of breast cancer. Previous research modified chalcone compounds into pyrazoline benzenesulfonamide derivatives (Modifina) which show activity as an ERα inhibitor. This study aimed to design novel pyrazoline benzenesulfonamide derivatives (PBDs) as ERα antagonists using in silico approaches. Structure-based and ligand-based drug design approaches were used to create drug target molecules. A total of forty-five target molecules were initially designed and screened for drug likeness (Lipinski’s rule of five), cytotoxicity, pharmacokinetics and toxicity using a web-based prediction tools. Promising candidates were subjected to molecular docking using AutoDock 4.2.6 to evaluate their binding interaction with ERα, followed by molecular dynamics simulations using AMBER20 to assess complex stability. A pharmacophore model was also generated using LigandScout 4.4.3 Advanced. The molecular docking results identified PBD-17 and PBD-20 as the most promising compounds, with binding free energies (ΔG) of −11.21 kcal/mol and −11.15 kcal/mol, respectively. Both formed hydrogen bonds with key ERα residues ARG394, GLU353, and LEU387. MM-PBSA further supported these findings, with binding energies of −58.23 kJ/mol for PDB-17 and −139.46 kJ/mol for PDB-20, compared to −145.31 kJ/mol, for the reference compound, 4-OHT. Although slightly less favorable than 4-OHT, PBD-20 demonstrated a more stable interaction with ERα than PBD-17. Furthermore, pharmacophore screening showed that both PBD-17 and PBD-20 aligned well with the generated model, each achieving a match score of 45.20. These findings suggest that PBD-17 and PBD-20 are promising lead compounds for the development of a potent ERα inhibitor in breast cancer therapy. Full article

Oxysterols such as 7-ketocholesterol (7KCh) contribute to the pathogenesis of autoimmune and chronic inflammatory diseases by inducing oxidative stress and promoting pro-inflammatory immune cell activation. Dendritic cells (DCs) play a central role in maintaining immune tolerance, and their dysregulation is a key driver of autoimmunity. Targeting DCs by using natural compounds offers a promising strategy to restore redox balance and suppress aberrant immune responses. This study investigated the immunomodulatory and antioxidant properties of Lupeol, a natural triterpenoid, in human monocyte-derived DCs exposed to 7KCh. Flow cytometry and cytokine profiling demonstrated that Lupeol preserved the immature, tolerogenic phenotype of DCs by promoting a dose-dependent increase in the anti-inflammatory cytokine IL-10. Lupeol also inhibited the 7KCh-induced upregulation of maturation markers (CD83, CD86) and suppressed the release of pro-inflammatory cytokines IL-1β and IL-12p70. Functionally, Lupeol-treated DCs directed T cell polarization toward an anti-inflammatory and regulatory profile while dampening the inflammatory responses triggered by 7KCh. This immunoregulatory effect was further supported by the decreased secretion of the pro-inflammatory cytokines IL-1β and IL-12p70 in DC culture supernatants. Mechanistic analyses using immunofluorescence showed that Lupeol alone significantly increased nuclear NRF2 levels and upregulated HO-1 expression. Western blot analysis further confirmed Lupeol’s ability to activate the KEAP1-NRF2 signaling pathway, as evidenced by increased expression of NRF2 and its downstream target, NQO1. The use of ML385, a selective NRF2 inhibitor, in ROS and cytokine assays supported the involvement of NRF2 in mediating the Lupeol antioxidant and anti-inflammatory effects in DCs. Notably, the oxidative burden induced by 7KCh limited the full activation of NRF2 signaling triggered by Lupeol. Furthermore, docking and MM/PBSA analyses revealed the specific interactions of Lupeol with the kelch domain of KEAP1. These findings suggest that Lupeol may serve as a promising orally available immunomodulatory agent capable of promoting tolerogenic DCs, offering potential applications in autoimmune and other chronic inflammatory diseases. Full article