This study investigated the potential of the indirubin-3'-oxime (I3O) compound to mitigate temperature-induced male infertility in Drosophila melanogaster. Elevated temperatures significantly reduced egg-hatching rates, but I3O supplementation improved these rates, suggesting it can partially restore fertility under heat stress. Additionally, I3O was found to inhibit soluble epoxide hydrolase (sEH), an enzyme involved in the metabolism of epoxyeicosatrienoic acids, which are vital for reproductive health. I3O exhibited sEH inhibitions with an IC50 value of 59.74 ± 0.41 µM. Enzyme kinetics revealed that I3O acts as a non-competitive inhibitor of sEH with a Ki value of 78.88 µM. Molecular docking showed strong interactions between I3O and key residues in the allosteric regions within the sEH enzyme, with a binding affinity of -9.2 kcal/mol. These interactions were supported by 100 ns molecular dynamics simulations, which confirmed the stability of the sEH-I3O complex.

This study investigates the potential effects of essential oils (EOs) in enhancing the efficacy of clindamycin against Methicillin-resistant Staphylococcus aureus (MRSA) using in vitro and computer simulations. The research seeks to identify essential oils that exhibit synergistic activity with clindamycin and determine their potential key active components.

Essential oils commonly used in traditional medicine were tested for their antimicrobial activity against MRSA. The minimum inhibitory concentration (MIC) was determined using in vitro microdilution assays. A synergistic test with clindamycin was performed, and molecular docking studies evaluated the interaction between a key compound (trans-cinnamaldehyde) and MRSA protein.

EOs from Cinnamomum verum, Rosmarinus officinalis, Salvia officinalis, and Thymus vulgaris demonstrated significant inhibitory and synergistic activities against MRSA, standard strain, and human clinical isolates. Gas Chromatography/Mass Spectroscopy identified trans-cinnamaldehyde, eucalyptol, and thymol as prominent antibacterial compounds. Molecular docking studies confirmed trans-cinnamaldehyde's strong binding to MRSA's AgrA protein, elucidating its enhanced efficacy.

The study underscores the potential of plant-based therapies to augment the effectiveness of conventional antibiotics like clindamycin in combating MRSA and addressing antibiotic resistance by integrating traditional plant remedies with modern medical approaches.

African swine fever is a highly lethal disease caused by the African swine fever virus (ASFV), posing a significant threat to the global pig industry, wherease no approved treatments are currently available. The ASFV DNA-binding protein, pA104R, plays a critical role in viral genome packaging and replication, making it a key target for drug discovery. Through structure-based virtual screening, we identified a polyphenolic compound, thonningianin A, which disrupts the pA104R-DNA binding and significantly inhibits ASFV replication. Mechanistic study revealed that thonningianin A binds to the DNA-binding region of pA104R, forming strong hydrogen bonds with H100 and occupying the vital DNA-binding residues K92, R94, and K97. In addition, we resolved the high-resolution (1.8 Å) structure of pA104R (PDB ID 9JS5), providing valuable insights for future drug screening. Together, these results demonstrate that thonningianin A holds great potential for the development of anti-ASFV drug, as a herb extract with favourable pharmacokinetic properties and safety.

Diabetic nephropathy (DN) is a diabetes mellitus (DM)-induced complication that poses high morbidity and mortality risks. The Astragalus and Salvia miltiorrhiza couplet medicines (AS) are commonly employed in DN clinical treatment in China, but their clinical efficacy and potential pharmacological mechanisms are yet to be evaluated.

A meta-analysis of 15 studies involving 1,443 patients was conducted. Furthermore, network pharmacology predicted components and targets, which were verified by molecular docking and in vivo validation.

In our meta-analysis, AS notably elevated clinical outcomes and renal function among patients with DN. Meanwhile, when the treatment duration exceeds 12 weeks, AS demonstrated a significant reduction in fasting blood glucose levels, indicating a time-dependent effect. Moreover, based on network pharmacology results, AS likely enhanced clinical outcomes by interacting with vital signaling pathways, including PI3K/Akt, MAPK, and NF-kappa B. Molecular docking studies have confirmed that PTGS2, the key therapeutic target of AS, can be closely combined with bioactive components GLY, quercetin, apigenin, and daidzein. Additionally, in vivo experiments have corroborated that AS can ameliorate renal function, UACR, and biomarkers associated with iron metabolism, such as GPX4, PTGS2, FTH1, and FTL1.

Through rigorous experimental validation, our study demonstrates AS's significant clinical efficacy in managing DN. Specifically, AS has been shown to enhance renal function, ameliorate renal fibrosis, and positively influence iron metabolism. Despite these promising outcomes, future research with a larger sample size must be conducted to further substantiate these findings.

This study investigates the mycochemical profile and biological activities of hydroethanolic (EtOH), chloroform (CHCl3), and hot water (H2O) extracts of Sanghuangporus lonicerinus from Uzbekistan. Antioxidant capacity was assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), NO, and FRAP assays, and in vitro hypoglycaemic effects were evaluated through α-amylase and α-glucosidase inhibition. Antiproliferative potential was explored by analysing the binding affinities of EtOH and H2O extracts to estrogen receptor α (ERα), ERβ, androgen receptor (AR), and glucocorticoid receptor (GR), with molecular docking providing structural insights. LC-MS/MS analysis revealed solvent-dependent phenolic profiles, with the EtOH extract containing the highest total phenolic content (143.15 ± 6.70 mg GAE/g d.w.) and the best antioxidant capacity. The EtOH extract showed significant hypoglycaemic effects, with 85.29 ± 5.58% inhibition of α-glucosidase and 41.21 ± 0.79% inhibition of α-amylase. Moderate ERβ binding suggests potential for estrogen-mediated cancer therapy, while strong AKR1C3 inhibition by the EtOH extract supports its therapeutic potential.

Chronic obstructive pulmonary disease (COPD) is characterized by restricted airflow that leads to significant respiratory difficulties. This progressive disease often results in diminished pulmonary function and the onset of additional respiratory conditions. Autophagy, a critical cellular homeostasis mechanism, plays a significant role in the exacerbation of COPD. In this study, we utilized various bioinformatics tools to identify autophagy-related genes activated by smoking in individuals with COPD. Furthermore, we explored the immune landscape of COPD through these genes, analyzing cell communication patterns using scRNA-seq data. This analysis focused on key pathways between epithelial cells and other cellular subpopulations with different autophagy scores, essential for understanding the initiation and progression of COPD.

Lespedeza bicolour Turcz. is a traditional medicinal plant with a wide range of ethnomedicinal values. The main components of L. bicolour essential oil (EO) were β-pinene (15.41%), β-phellandrene (12.43%), and caryophyllene (7.79%). The EO of L. bicolour showed antioxidant activity against ABTS radical and DPPH radical with an IC50 value of 0.69 ± 0.03 mg/mL and 10.44 ± 2.09 mg/mL, respectively. The FRAP antioxidant value was 81.96 ± 6.17 μmol/g. The EO had activities against acetylcholinesterase, α-glucosidase, and β-lactamase with IC50 values of 309.30 ± 11.16 μg/mL, 360.47 ± 35.67 μg/mL, and 27.54 ± 1.21 μg/mL, respectively. Molecular docking showed methyl dehydroabietate docked well with all tested enzymes. Sclareol and (+)-borneol acetate showed the strongest binding affinity to α-glucosidase and β-lactamase, respectively. The present study provides a direction for searching enzyme inhibitors for three tested enzymes and shows L. bicolour EO possesses the potential to treat a series of diseases.

In light of searching for new breast cancer therapies, DNA-targeted small molecules were rationally designed to simultaneously bind DNA and inhibit human dihydrofolate reductase (hDHFR). Fourteen new arylidene-hydrazinyl-1,3-thiazoles (5-18) were synthesised and their dual DNA groove binding potential and in vitro hDHFR inhibition were performed. Two compounds, 5 and 11, proved their dual efficacy. Molecular docking and molecular dynamics simulations were performed for those active derivatives to explore their mode of binding and stability of interactions inside DHFR active site. Anti-breast cancer activity was assessed for 5 and 11 on MCF-7 cells using MTX as reference. IC50 measurements revealed that both compounds were more potent and selective than MTX. Cytotoxicity was examined against normal skin fibroblasts to examine safety and selectivity Moreover, mechanistic studies including apoptosis induction and wound healing were performed. Further in silico ADMET assessment was conducted to determine their eligibility as drug leads suitable for future optimisation and development.

This study explores the therapeutic potential of Abrus precatorius leaves in arthritis treatment using computational methods and LC-MS analysis.

The plant material was taxonomically authenticated, and phytochemical analysis identified bioactive compounds such as alkaloids, flavonoids, and triterpenoids.

Swiss ADME analysis confirmed that multiple compounds complied with Lipinski's Rule of Five, while OSIRIS software indicated minimal toxicity. PASS analysis predicted anti-inflammatory and antioxidant activities. Molecular docking simulations of Abrine with key rheumatoid arthritis (RA) targets revealed strong binding affinities, suggesting potential mechanisms for RA treatment.

This research highlights the medicinal potential of Abrus precatorius leaves and emphasizes the importance of computational tools in understanding their pharmacological properties for arthritis management.

This study investigates the fluorescence behavior of the synthesized compound (E)-1-(4-chloro-2-(((2-hydroxynaphthalen-1-yl) methylene) amino) phenyl)-3-(naphthalen-1-yl) urea (3DB) in various solvents. A significant increase in fluorescence intensity was observed when transitioning from ethanol to less polar solvents like CH2Cl2, CHCl3, and CCl4, indicating enhanced fluorescence due to reduced non-radiative processes. Emission wavelengths remained stable with minor shifts (5-6 nm), while significant blue shifts in absorption occurred in water due to strong hydrogen bonding. Fluorescence spectra showed red shifts (519 nm in water, 508 nm in glycerol, and 486 nm in ethylene glycol), highlighting the impact of hydrogen bonding on electronic transitions. Emission intensity in water was six times higher than in ethylene glycol, suggesting that strong hydrogen bonds stabilize the excited state. The study also revealed that 3DB exhibits a large Stokes shift, avoiding reabsorption of emitted light (inner filter effect). Fluorescence was completely quenched by low concentrations of copper ions, demonstrating 3DB's potential as a copper sensor. Density functional theory (DFT) and time-dependent DFT (TDDFT) calculations indicated that luminescence quenching in the Cu(II) complex is due to intramolecular charge transfer (ICT). Additionally, 3DB formed stable complexes with DNA and β-cyclodextrin (β-CD), with binding constants (Kb) of 1.30 × 103 M-1 and 1.89 × 103 M-1, respectively, and negative Gibbs free energy values, indicating spontaneous interactions. Fluorescence spectroscopy confirmed DNA binding, showing a 49.62 % increase in intensity and a 4 nm blue shift, consistent with groove-binding. Docking studies further supported favorable interactions with DNA. These results underscore 3DB's potential in sensing, imaging, environmental monitoring, and biological applications.

Recent advancements in data technology offer immense opportunities for the discovery and development of new enzymes for the green synthesis of chemicals. Current protein databases predominantly prioritize overall sequence matches. The multi-scale features underpinning catalytic mechanisms and processes, which are scattered across various data sources, have not been sufficiently integrated to be effectively utilized in enzyme mining. In this study, we developed a sequence- and taxonomic-feature evaluation driven workflow to discover enzymes that can be expressed in E. coli and catalyze chemical reactions in vitro, using alcohol oxidase (AOX) for demonstration, which catalyzes the conversion of methanol to formaldehyde. A dataset of 21 reported AOXs was used to construct sequence scoring rules based on features, including sequence length, structural motifs, catalytic-related residues, binding residues, and overall structure. These scoring rules were applied to filter the results from HMM-based searches, yielding 357 candidate sequences of eukaryotic origin, which were categorized into six classes at 85 % sequence similarity. Experimental validation was conducted in two rounds on 31 selected sequences representing all classes. Among these selected sequences, 19 were expressed as soluble proteins in E. coli, and 18 of these soluble proteins exhibited AOX activity, as predicted. Notably, the most active recombinant AOX exhibited an activity of 8.65 ± 0.29 U/mg, approaching the highest activity of native eukaryotic enzymes. Compared to the established UniProt-annotation-based workflow, this feature-evaluation-based approach yielded a higher probability of highly active recombinant AOX (from 8.3 % to 19.4 %), demonstrating the efficiency and potential of this multi-dimensional feature evaluation method in accelerating the discovery of active enzymes.

This study assessed the impact of curing salts and maturation times on peptide production and bioactivity in dry-cured hams using in vitro and in silico methods. Ninety-six hams underwent six curing treatments and two maturation stages (38 % and 42 % weight loss). Mass spectrometry identified bioactive peptides, while in silico tools predicted their bioactivities. Reduced sodium nitrifying salts (treatment IX) and 42 % weight loss showed the most significant results, enhancing low-molecular-weight peptides generation (EE, VG, VD) linked to high functionality. Antioxidant and antihypertensive activities were prominent in samples with 42 % weight loss. Peptides under 1.5 kDa were more abundant at advanced maturation stages. In silico analyses predicted ACE and DPP-IV inhibition and antioxidant effects. Dipeptides like DG, ES, and DV showed similarities to FDA-approved molecules, suggesting potential therapeutic uses. The study highlights those specific treatments boost biopeptides formation, requiring further research on their potential as functional foods or therapeutic agents.

Ginger (Zingiber officinale) is widely recognised for its functional benefits, primarily attributed to its diverse phytochemicals. However, its proteome remains largely unexplored. This study hypothesised that isolated peptides may exhibit different bioactivities or more targeted mechanisms of action and could be investigated at a molecular level. Proteins were enzymatically hydrolysed under five conditions, and peptides were identified using LC-MS/MS. In silico screening suggested antioxidant, ACE-inhibitory, and antibacterial properties, further assessed through molecular docking and in vitro validation. 41 potentially bioactive peptides were identified. In vitro assays confirmed these properties for selected peptides, P1 (GSPVWIIPEPT), P2 (FASYPVKK), P3 (GPEKIFYDGPYL), and P4 (IAISPSYPIK). Notably, P4 exhibited potent mixed-type ACE-inhibition and bacteriostatic effects. Molecular docking provided mechanistic insights into these interactions. These findings highlight ginger as a promising source of bioactive peptides while underscoring the need to complement AI tools with in vitro and in vivo validations due to observed discrepancies.

Six enantiomers of three racemic sigma-1 receptor (σ1R) ligands were resolved, and absolute configuration was determined. Their high σ1R potency and selectivity were determined through in vitro binding assays, further validated by molecular docking analysis. Central Nervous System Multiparameter Optimization algorithm (CNS MPO) predicts efficient brain penetration for these enantiomers. Six C-11 radiotracers were radiosynthesized successfully, ex vivo biodistribution in rats showed that (-)-[11C]7 had high brain uptake of ∼4.8-fold for 5 min versus 60 min. Mouse brain PET imaging studies showed (-)-[11C]7 and (-)-[11C]16 have in vivo binding specificity for σ1R. Macaque PET scans showed high brain uptake for all six radiotracers, with (-)-[11C]7 peaked at ∼45 min (SUV 2.5), possessing the best washout kinetics and highest cerebellum-to-white matter ratio (∼3.1), in agreement with in vitro or ex vivo measures of σ1R expression. Radiometabolite analysis showed that no newly formed radiometabolite was observed post-injection of (-)-[11C]7. Our data suggest that further evaluation is warranted to determine that (-)-[11C]7 is a suitable PET radiotracer for imaging σ1R in the brain of animal and human.

In the face of escalating climate change challenges, there is an imperative to enhance crop resilience and productivity. The plant growth regulator 6-benzylaminopurine (BA[P]) shows considerable potential in agriculture, yet its practical use is hampered by low water solubility and susceptibility to light and heat instability. This study addresses these limitations and addresses the transformative potential of complexing 6-BAP with cyclodextrins (CDs) or CD-based nanosponges (CD-NS). Calculations of inclusion constants of various CDs gave the opportunity to synthetize the best CD-NSs for BAP complexation, being β-CD the best one (KF = 289.50 ± 23.16 M-1). A general enhancing effect observed for CD-based polymers than monomeric ones: The complexation efficiency was determined and compared (67 % monomers vs average 89 % for the polymers), as well as their improved water solubility, controlled release (βNS-CDI > β-CD > βNS-CA), and increased bioavailability in vitro. Furthermore, CDs and CD-NS offer effective protection against thermal degradation, potentially extending the shelf life of 6-BAP formulations, which is shown by an enlarged effect in shoots of Prunus salicina LIndl, with applications in agriculture. Thus, shoots cultured in vitro in culture media supplemented with these complexes showed an improvement in the shoot production rate along with an increase in the endogenous BAP and riboside BAP. With the main objective to demonstrate the increase of capacity of BAP-based complexes, this research lays the foundation of the eco-friendly use of dextrin-based polymers for micropropagation improvement.

This study investigates the impact of tryptophan substitution on the properties of the Medisin family peptide MS-PT. By substituting hydrophobic amino acids in MS-PT1 with tryptophan, a series of derivative peptides were synthesized. Among them, the 7W peptide stood out with its unique N-terminal random curl and α-helix structure. In vitro, 7W effectively inhibited the secretion of pro-inflammatory cytokines like IL-6 and TNF-α in LPS-induced Membrane-Proximal Macrophages (MPMs) by blocking the MAPK/NF-κB signaling pathway. It also exhibited stronger antimicrobial activity against Gram-positive bacteria compared to the parent peptide MS-PT1, with good safety as indicated by a low hemolysis rate. In vivo, in the CLP-induced sepsis mouse model, 7W alleviated lung and liver injury, suppressed the expression of inflammatory factors in serum and tissues, and had a relatively long plasma half-life of 46.8 h. Mechanistically, 7W interacted preferentially with bacterial mimic membranes and LPS, and its anti-inflammatory effect might be mediated by binding to TLR4. These findings not only clarify the role of tryptophan substitution in modulating peptide properties but also offer a new strategy for the development of multifunctional antimicrobial peptides, suggesting that 7W has great potential as a therapeutic agent for sepsis and other inflammatory diseases.

Neurodegenerative diseases such as Parkinson's and Alzheimer's lead to the gradual decline of the nervous system, resulting in cognitive and motor impairments. With an aging population, the prevalence and associated healthcare costs are anticipated to rise. Misfolded protein aggregates are central to these diseases, disrupting cellular function and causing neuronal death. Preventing these toxic aggregates could preserve neurons and slow disease progression. Understanding how to inhibit protein aggregation is crucial for developing effective treatments. We explored the effect of nalidixic acid (NA) on protein aggregation using human serum albumin (HSA) as model protein. In vitro assays demonstrated that NA significantly reduced ThT fluorescence by 47.10 % and decreased turbidity by 63.07 %. NA also protected the protein's hydrophobic surfaces. The α-helical content of HSA dropped from 56.23 % to 11.43 % but was restored to 38.53 % with NA. We then utilized advanced molecular simulations to understand the kinetics and mechanism of aggregation inhibition by NA. Binding studies showed that NA attaches to HSA's subdomain IIA with a binding energy of -7.8 kcal/mol through hydrogen bonds, Van der Waals forces, and hydrophobic interactions. Molecular simulations confirmed the stability of HSA-NA complex. Additionally, NA increased solvent accessibility of HSA282-292 oligomers, reduced hydrogen bonding, and prevented β-sheet formation. Compared to existing anti-aggregation strategies, NA offers a promising alternative with its potential therapeutic applications in neurodegenerative diseases by stabilizing protein structures and preventing misfolding. These findings highlight NA's potential as a candidate for inhibiting protein aggregation and offer insights for therapeutic approaches. Further experimental studies utilizing in vivo models are needed to validate the anti-aggregation potential of NA.

A chemical investigation of the fruiting bodies of Fomitopsis pinicola was conducted, resulting in the isolation of 51 compounds, which included 16 previously undescribed lanostane triterpenes (1-14, 16-17), 30 known analogs (15, 18-46) as well as two sterols (47-48) and three diterpenes (49-51). Comprehensive analyses utilizing 1D, 2D NMR, MS and IR spectroscopy and DFT calculations of 13C NMR chemical shifts have elucidated the structures of the compounds in question. Two undescribed compounds in addition to fomitosides F, G and K showed cytotoxicity against MCF-7 cell line with IC50 values ranging from 11.01 to 31.92 μM. Meanwhile, these isolates showed α-glucosidase inhibitory activity, and compound 7 showed the IC50 value of 9.22 μM.

Benzo[c]phenanthridine alkaloids are known for their stabilizing effects on non-canonical DNA structures, particularly G-quadruplexes (G4s). In this study, the interaction of fagaronine, a rare benzo[c]phenanthridine alkaloid, with several DNA structures (including B-DNA, parallel, antiparallel and hybrid G4s) is studied using molecular fluorescence and circular dichroism (CD) spectroscopy. It has been found that fagaronine significantly enhances the stability of all tested G4 conformations. Furthermore, a study by NMR spectroscopy provided valuable information on the mechanism of interaction of the ligand with the parallel G4 structure adopted by Pu22T14T23, a sequence mutated with respect to that found within the promoter region of the c-myc gene. Remarkably, when compared with data reported in the literature, fagaronine appears to exhibit one of the strongest G4 thermal stabilization effects ever recorded for a small ligand.

Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase that plays a crucial role in cell proliferation, migration, and signal transduction. FAK is overexpressed in metastatic and advanced-stage cancers, where it is considered a key kinase in cancer growth and metastasis. However, recent research has revealed that FAK activity decreases in various diseases. we aimed to identify compounds that could enhance FAK activity using structure-based virtual screening and artificial intelligence models from a vast chemical database. We began with an extensive chemical database containing over 10 million compounds and used our newly developed pipeline to screen candidate molecules. To select compounds structurally similar to ZINC40099027 (ZN27), a known FAK activator, we calculated Tanimoto Similarity scores and chose compounds with a score of at least 0.8. Clustering was performed using K-means based on the molecular properties. Subsequently, we utilized docking simulation, deep learning and SAScorer to evaluate and predict the protein-ligand docking affinity and physicochemical properties of the candidate compounds. The deep learning models were selected as state-of-the-art models: GLAM predicts the blood-brain barrier permeability of FAK, and elEmBERT predicts the potential toxicity of compound. The combined results were used to create an evaluation matrix. We selected 10 promising candidate compounds from the initial dataset of 10 million. To evaluate the stability of these top 10 candidate compounds in interaction with the FAK protein, we conducted Molecular Dynamics (MD) simulations. We performed a molecular dynamics simulation for a total of 50 ns and identified the top three promising candidate compounds.

Cancer is a significant health and economic concern worldwide. Prostate cancer (PC) ranks as the fourth leading cause of global death and is the second most prevalent malignancy in males. Androgens are essential for the progress and growth of the prostate gland. PC is caused by androgens binding to receptors, which activates genes that promotes the development of PC. Nilutamide (NLM) is an antiandrogen medicine used in the treatment of PC. However, throughout treatment, it induces various toxicities and leads to resistance in patients. The objective of the work was to designed and evaluated safer NLM analogues using computational approaches with optimized pharmacokinetic profiles and less toxicity. Newer bioisosteres of the designed NLM analogues and their ADMET scores were calculated using the MolOpt and ADMETlab 3.0 tools, respectively. We conducted docking investigations of the designed ligands using AutoDock Vina software. The MolOpt web server produces 1575 bioisosteres of NLM using the scaffold transformation method. The 47 bioisosteres were selected based on pharmacokinetic profiles, drug likeness (DL) and drug score (DS) prediction scores and were determined to be optimum to excellent in comparison to NLM. The analogues NLM28, NLM31, NLM34, NLM38, NLM40, NLM44, NLM45, and NLM47 exhibited favorable interactions and docking scores with the protein (PDB ID: 2AM9). The molecular dynamics (MD) simulation results revealed that the NLM34 and NLM40 complexes were found stable during the 100 ns run. The findings indicate that the NLM analogues, particularly NLM34 and NLM40 have the potential to be used as promising antiandrogen agents for PC therapy.

Adverse Outcome Pathways (AOPs) in toxicology describe the sequence of key events from chemical exposure to adverse outcomes, facilitating the development of predictive models. The EU ONTOX project uses this framework to predict liver, developmental brain, and kidney toxicity without animal testing. Focusing on Molecular Initiating Events (MIEs), more concretely on the interaction of chemicals with key proteins, we have developed an automated workflow for docking small molecules onto over 20 pre-processed protein structures, implemented in the online tool DockTox. This tool generates conformers of small molecules, performs docking on MIE-associated proteins, and provides binding energy, interacting residues, and interaction maps. Additionally, it compares the interactions to a reference list of known ligands, producing an interaction fraction as an additional similarity measure. Evaluation of the docking workflow's predictive performance on Peroxisome Proliferator-Activated Receptor α (PPARα) showed that interaction fraction values are more informative than binding energy alone for distinguishing binders from non-binders. This unique feature enhances the understanding of target protein interactions. DockTox supports the virtual screening of small molecules targeting MIE-associated proteins, offering insights into binding energies and interaction profiles. It is a valuable tool for anticipating adverse outcomes from chemical exposure in a tiered risk assessment approach.

Peripheral nerve injury enhances mitochondrial translocator protein (TSPO) expression in the spinal cord and dorsal root ganglia (DRG), which is associated with neuroinflammation and mitochondrial dysfunction contributing to chronic pain development. Here, we investigate the effect of TSPO ligand Etifoxine, on the development of chronic pain and motor dysfunction following sciatic nerve injury. Mechanical and thermal sensitivity, as well as motor function, were measured in rats before and after sciatic nerve crush (SNC). Rats were treated with the Etifoxine (50 mg/kg, twice daily) for one week. At the end of the experiment, RT-PCR and immunohistochemistry (IHC) were performed to assess mitochondrial stress and neuroinflammation. Additionally, high-resolution respirometry (O2k) was used to evaluate mitochondrial function in the spinal cord following mitochondrial permeability transition pore (mPTP) induction by Ca2+. Etifoxine treatment post-SNC alleviated mechanical and thermal hypersensitivity, as well as motor dysfunction in rats. In addition, Etifoxine treatment modulates neuroinflammation and mitochondrial stress. Specifically, we found a significant reduction in microglia presence and the transcription of pro-inflammatory cytokines (TNFα, IL-6, IL-1β) in the DRG and spinal cord of the SNC/etifoxine-treated group. Furthermore, Etifoxine treatment prevent the decline in mitochondrial respiration, including non-phosphorylation, ATP-linked respiration, and maximal respiration, after mPTP induction by Ca2+. Our findings suggest that TSPO-ligand Etifoxine protects against motor dysfunction and the development of chronic pain by reducing neuroinflammation and apoptosis in the DRG and spinal cord. Importantly, the beneficial effects of TSPO-ligands are reflected in the restoration of the mitochondrial function under challenging conditions.

Drug-target affinity prediction is a fundamental task in the field of drug discovery. Extracting and integrating structural information from proteins effectively is crucial to enhance the accuracy and generalization of prediction, which remains a substantial challenge. This paper proposes a pocket-based multimodal deep learning model named PocketDTA for drug-target affinity prediction, based on the principle of "structure determines function". PocketDTA introduces the pocket graph structure that encodes protein residue features pretrained using a biological language model as nodes, while edges represent different protein sequences and spatial distances. This approach overcomes the limitations of lack of spatial information in traditional prediction models with only protein sequence input. Furthermore, PocketDTA employs relational graph convolutional networks at both atomic and residue levels to extract structural features from drugs and proteins. By integrating multimodal information through deep neural networks, PocketDTA combines sequence and structural data to improve affinity prediction accuracy. Experimental results demonstrate that PocketDTA outperforms state-of-the-art prediction models across multiple benchmark datasets by showing strong generalization under more realistic data splits and confirming the effectiveness of pocket-based methods for affinity prediction.

Sixteen indole alkaloids were isolated from the hook-bearing stems of Uncaria rhynchophylla (Rubiaceae family), including seven undescribed ones, uncarialines F-L (1-5, 7, and 8), and a naturally occurring alkaloid, 3-epicorynanthine (6). Among them, alkaloids 1 and 2 were identified as rare quaternary ammonium alkaloids, and alkaloid 7 exhibited an unprecedented indole alkaloid framework. Their structures were characterized by a comprehensive analysis of NMR, MS, ECD and single-crystal X-ray diffraction. Notably, alkaloid 5 demonstrate potent inhibitory activity against α-glucosidase, with an IC50 value of 18.45 ± 0.77 μM. Furthermore, the inhibitory kinetics of α-glucosidase revealed that alkaloid 5 belong to the mix inhibition type. Molecular docking analysis showed that alkaloid 5 possessed superior binding affinity with α-glucosidase (-10.7 kcal/mol).

Diabetes is known to cause severe pancreatic inflammation and reduce insulin levels, leading us to investigate the effects of prodigiosin (PG), a red, heterocyclic bacterial compound extracted from Serratia marcescens. The physicochemical and nutritional conditions, along with the extraction solvents for PG, have been optimized for efficient production. PG was produced through bacterial culture, purified by high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC), characterized by Fourier-transform infrared spectroscopy (FTIR) and ultraviolet (UV) spectroscopy. In vitro, PG effectively inhibited key inflammatory enzymes, such as phospholipase A2 (PLA2) and elastase (ELA), in a dose-dependent manner, achieving maximum inhibition rates of 85.3 and 91.4 % at concentrations of 320 µg/mL, with IC₅₀ values of 63 µg/mL and 54.7 µg/mL, respectively. PG also exhibited a maximum inhibition of 82.4 % for myeloperoxidase (MPO) at a concentration of 160 µg/mL, with an IC₅₀ value of 25.9 µg/mL. This indicates that PG is a good candidate for treating these two metabolic diseases. Moreover, PG shows a significant ability to activate insulin signaling through its capacity to stimulate protein tyrosine phosphatase 1B (PTP1B) and inhibit dipeptidyl peptidase-4 (DPP-4), with IC₅₀ values of 67 and 28 µg/mL, respectively, compared to the specific inhibitors CLM and STG (with IC₅₀ values of 19 and 27 µg/mL, respectively). These powerful affinities, stability, and the durability of PG inhibition of these enzymes are confirmed by the determination of binding energy, ligand efficiency, and estimated inhibition constant (Ki). Conclusion: PG benefits from sustainable, cost-effective biological production and exhibits potent anti-inflammatory, antioxidant, and anti-diabetic properties, positioning it as a promising candidate for pharmaceutical and food applications.

Nephrolithiasis (kidney stones) affects nearly 13 % of the global population, with a high recurrence rate posing significant challenges. Current remedies often fail to prevent recurrence, necessitating new therapeutic approaches. This study explores phytochemicals with potential protective effects against nephrolithiasis using similarity searching, network pharmacology, and molecular docking methods. Six anti-nephrolithiatic parent molecules were identified through a literature review. Structural similarity searches yielded 67 related compounds, which were screened using Lipinski' s rule of five, along with ADME (absorption, distribution, metabolism, excretion) parameters and toxicity profiles, and subsequently compared with standard drugs. The standard drug offered poor results; therefore, we aimed to overcome this limitation by searching for phytochemicals with favorable ADMET properties. Shortlisted compounds and nephrolithiasis-related targets were analyzed using Swiss Target Prediction and GeneCards. Hub genes were identified via Cytoscape' s Cytohubba plugin and subjected to Gene Ontology (GO) and KEGG pathway analysis. Molecular docking evaluated the binding of phytochemical ligands to disease proteins. Five phytochemicals namely 4- 4-Vinylguaiacol, anethole, isoeugenol, nadolol, and silibinin, were identified as potential candidates. Network pharmacology revealed 191 common targets between these compounds and nephrolithiasis. GO analysis highlighted key biological processes (response to organic substances, chemical stimuli), cellular components (nuclear lumen, nucleoplasm), and molecular functions (enzyme binding, catalytic activity). KEGG pathway analysis identified pathways in cancer, hepatitis B, and Kaposi sarcoma-associated herpesvirus infection as relevant to nephrolithiasis. Molecular docking demonstrated strong binding affinities between the shortlisted phytochemicals and disease targets. The multi-level screening and molecular docking findings highlight 4-Vinylguaiacol, anethole, isoeugenol, nadolol, and silibinin as promising therapeutic agents for nephrolithiasis. Among these, silibinin was tested for the in-vitro cytotoxicity assay based on the docking score. Importantly, in vitro validation using NRK-52E cells confirmed nephroprotective efficacy of silibinin. While calcium oxalate crystal exposure significantly reduced cell viability to below 50 %, co-treatment with silibinin improved cell survival to approximately 70 %, underscoring its potential to mitigate oxalate-induced cytotoxicity. Further experimental studies are required to validate these findings.

Triple-negative breast cancer (TNBC) is a rare and highly metastatic form of cancer. Honokiol (HNK), a biphenolic compound, has been utilized in TNBC treatment, though its specific targets remain unclear. This study aimed to elucidate the effects of HNK on TNBC by combining network pharmacology predictions and experimental validation to uncover its mechanisms. MDA-MB 231 and MDA-MB 468 cells were pre-treated with varying doses of HNK for 24 h. Cell viability, proliferation, and apoptosis were assessed using CCK8 and FACS assays, whereas a wound healing assay was used to evaluate cell migration. A tubule formation assay was used to assess blood vessel formation in HUVECs. Additionally, in vivo activity was confirmed using a zebrafish xenograft model. Network pharmacology and molecular docking predicted active ingredients, key targets, and potential mechanisms of HNK against TNBC. Results indicated that HNK induces apoptosis in MDA-MB 231 and MDA-MB 468 cells and inhibits their migration and proliferation. Furthermore, HNK suppressed blood vessel formation. Zebrafish xenograft experiments validated HNK's inhibitory effect on TNBC cells in vivo. Network pharmacology identified 36 potential HNK targets against TNBC, including HSP90AA1, AKT1, EGFR, ERBB2, HSP90AB1, PGR, MDM2, HDAC1, NR3C1, and MAPK14. Key signaling pathways such as PI3K-Akt, MAPK, Rap1, Ras, and FoxO were implicated in HNK's anti-TNBC mechanism. Molecular docking demonstrated spontaneous interactions between HNK and the targeted proteins. In conclusion, HNK may reduce angiogenesis by blocking the EGFR and HSP90AB1 pathways thereby decreasing proliferation and increasing apoptosis in TNBC cells.

Ubiquitous per- and poly-fluoroalkyl substances (PFAS) threaten human's health and attract worldwide attention. PFAS-mediated toxicity involves adverse effects of PFAS on proteins, and assessment of PFAS-protein binding interactions helps to explain PFAS' adverse effects on human health. In-silico modeling can generate information and decrease experimental costs. Accordingly, in this study, molecular docking was used to determine the binding affinities of 430 PFAS with human serum albumin (HSA), peroxisome proliferator-activated receptor gamma (PPARγ), and transthyretin (TTR). Specifically, analytic hierarchy process, fuzzy comprehensive evaluation, and quantitative structure-activity relationship model were used to assess and predict the binding affinities between PFAS and HSA, PPARγ, and TTR. The binding patterns were determined by defining "PEOE_RPC-, E_vdw, MNDO_LUMO, and vsurf features" as key factors related to charge, energy and shape characteristic of PFAS. Finally, Kronecker-regularized least squares (Kron-RLS) model was applied to predict the binding affinities between PFAS- and G protein-coupled receptor 40 (GPR40), as a new target for prediction. Results showed that the Kron-RLS model exhibited good performance and generated precise predictions (R2 = 0.94). In conclusion, this study demonstrated that computational simulations could be used to aid the scientific management of the growing number of PFAS, and could be broadened to include a wide range of environmental contaminations.

The mangosteen pericarp contains unstable non-acylated ACNs, rendering it prone to degradation. Therefore, intermolecular copigmentation of semi-purified ACNs (SPA) with tartaric acid (SPA-TA), sinapic acid (SPA-SA), catechin (SPA-CE), and sucrose (SPA-SU) in 1:5 and 1:10 M ratios were used to increase their stability during storage for 77 days at 25 ± 1 °C in pH 3 buffer solution. The SPA-TA1:5 complex showed the significant highest stability of total monomeric ACN content (TMAC) with a half-life (t1/2) = 56.9 days, cyanidin-3-O-sophoroside (C3S) with t1/2 = 48.1 days and color retention (69.80 %) compare to SPA with TMAC (t1/2 = 37.4), C3S (t1/2 = 13.3) and color retention (57.2 %) after 49 days (p < 0.05). The thermal stability of SPA-TA1:5 at 60 °C improved after high-pressure processing (HPP) at 300 and 500 MPa for 10 min. Fourier-transform infrared spectroscopy (FT-IR) and molecular docking indicate copigmentation interactions, including hydrogen bonding and π-π interactions. This study demonstrates a sustainable method to stabilize non-acylated ACNs, offering a natural alternative to synthetic dyes for food and beverage applications.

Modified cyclodextrins (CDs) are cyclic oligosaccharides with many applications in drug delivery, catalysis, and as active pharmaceutical ingredients. In general, they exist as distributions of structurally diverse molecules rather than single-isomer compounds. Their performance depends on the number of glucopyranose units (GPUs), and the type, number, and position of chemical substitutions in their hydroxyl groups. Effectively targeting individual species within these distributions is essential for optimizing CDs for specific applications. Computational techniques can generate large datasets to AI-driven structural optimization, but the absence of a standardized nomenclature system for modified CDs presents a major barrier to progress in this direction. This lack of consensus limits effective communication, data sharing, automation, and collaboration. To address this, a clear and extensible nomenclature for modified CDs is proposed. In this framework, GPUs are treated like amino-acid residues, with unsubstituted GPUs as reference building-blocks and substituted ones considered as mutations. This approach precisely defines substitution types and patterns, resolves cyclic permutation ambiguities, and offers versatility for both simple and complex modifications, including chiral center alterations and covalently linked CD oligomers. By introducing this standardized nomenclature, we aim to enhance molecular design, improve reproducibility, and streamline both experimental and computational research in the CD field.

Aldose reductase (AR), a key enzyme in the polyol pathway, contributes to diabetic complications through oxidative stress and cellular damage. We investigated the inhibitory potential of coumarins from Ruta chalepensis as AR inhibitors, combining experimental and computational approaches. Among studied coumarins, aegelinol demonstrated the strongest AR inhibition with a mixed inhibition mode (IC50 = 3.75 ± 0.11 μM, Kᵢ = 3.04 ± 0.82 μM), approaching the potency of the positive control quercetin (IC50 = 2.22 ± 0.27 μM). Marmesinin and gelseminic acid also showed notable inhibition (IC50 = 5.32 ± 0.15 μM, 5.82 ± 0.61 μM, respectively), with noncompetitive binding mechanisms (Kᵢ = 4.86 ± 0.35 μM and 4.46 ± 0.52 μM), suggesting allosteric binding. Docking highlighted key interactions with critical AR residues, while molecular dynamics simulations provided insights into the stability and dynamics of AR-ligand complexes. Various MD parameters confirmed structural integrity, with the aegelinol-AR complex exhibiting the highest stability. MM/PBSA calculations supported these findings, showing the most favorable binding free energy for aegelinol, followed by marmesinin and gelseminic acid. Potential energy landscape analyses showed that aegelinol forms the most stable AR complex with the deepest energy basin. ADMET analysis confirmed aegelinol as a promising lead due to its high gastrointestinal absorption, BBB permeability, and balanced lipophilicity. Thus, Aegelinol, marmesinin, and gelseminic acid show strong potential as AR inhibitors, with aegelinol as the leading candidate for therapeutic development. These findings highlight Ruta chalepensis as a promising source of bioactive coumarins for targeted therapies against diabetic complications.

β-N-acetylglucosaminidase (NagZ) plays an important role in the bacterial cell wall biosynthetic pathway. Inhibiting its activity could potentially impede bacterial growth. We report a study on the design and synthesis of cinnamoyl amides derived from rosmarinic acid (RA), and their enzymatic, antibacterial activity against NagZ and Pseudomonas aeruginosa respectively. In vitro enzyme activity determination showed that the best synthetic RA analogues displayed higher inhibitory activity than that of parent RA, in the same range than the most potent NagZ inhibitors reported so far. Remarkably, compounds 11h and Br-6 displayed interesting binding affinity values with Ki=3.3 ± 0.5 and 3.5 ± 1.0 μM, respectively. Docking simulations evidenced significant binding interactions of cinnamoyl amide derivatives with the active site of NagZ. Moreover, kinetic evaluations indicated these compounds displayed competitive behavior. Additionally, MICs of 11h and Br-6 combined with two β-Lactam antibiotics (imipenem and ceftazidime) were evaluated against P. aeruginosa by microdilution checkerboard assay, establishing that antibacterial agents show synergistic effects. In vivo antibacterial efficacy assay using a full-thickness skin defect model with P. aeruginosa infection confirmed these observations.

The C-C chemokine receptor type 5 is a G protein-coupled receptor expressed on various immune cells, playing a crucial role in inflammation and chemotaxis. Beyond its physiological functions, C-C chemokine receptor type 5 is implicated in numerous diseases, including cardiovascular, central nervous system, immune system, and infectious diseases, as well as in the progression of cancer. The therapeutic potential of C-C chemokine receptor type 5 inhibition has been demonstrated by antagonists targeting the extracellular domain, notably maraviroc, a Food and Drug Administration-approved Human Immunodeficiency Virus entry inhibitor. However, challenges such as suboptimal pharmacokinetics and efficacy necessitate new antagonists with unique modes of action. Recent advancements in G protein-coupled receptor structural characterization have identified a novel intracellular allosteric binding site in chemokine receptors. This study introduces a series of disubstituted [1,2,5]oxadiazolo-[3,4-b]pyrazines targeting the intracellular allosteric binding pocket of C-C chemokine receptor type 5. Among these, compound 3ad emerged as a promising C-C chemokine receptor type 5-selective allosteric antagonist with a half-maximal inhibitory concentration of 1.09 μM and an almost 30-fold selectivity over C-C chemokine receptor type 2. Molecular dynamics simulations and a competition assay with a Gαq11 mimetic were used to confirm the intracellular binding mode of these compounds. This novel class of C-C chemokine receptor type 5-selective intracellular antagonists offers a foundation for developing molecular tools and therapeutic agents, potentially overcoming the limitations of current extracellular C-C chemokine receptor type 5 antagonists.

Herein, a highly efficient and recyclable biocatalyst was developed using stabilized enzyme aggregates on amino-functionalized magnetic biochar for removing persistent organic pollutants from water. The biochar derived from biomass featured abundant hydroxyl functional groups, after functionalization with amino functional groups and magnetic nanoparticles, it was employed for laccase immobilization via enzyme electrostatic adsorption, precipitation and cross-linking in a favorable orientation. This immobilized enzyme aggregates exhibited enhanced pH tolerance, thermal and storage stability than free enzyme. Complete removal of 20 mg/L bisphenol A was achieved within 60 min via C-C bond cleavage and hydroxylation. Notably, the removal efficiency remained at approximately 90 % even after six cycles. Furthermore, this biocatalyst was also successfully applied to efficiently remove other various persistent organic pollutants and demonstrated applicability in real environmental water samples. This study highlights the substantial potential of enzyme-based biocatalysts, presenting a sustainable and efficient approach for water purification and biomass resource recovery.

The chemical structures of the parental compounds of flavonoids from Boesenbergia rotunda were modified by conjugation with cinnamic acid to form cinnamoyl-flavonoid hybrid derivatives with enhanced anti-inflammatory and SARS-CoV-2 Mpro-inhibitory properties. Cinnamoyl-flavonoid hybrid derivatives 6 and 10 showed the potential to inhibit SARS-CoV-2 Mpro with IC50 values of 52.49 and 22.62 μM. Compounds 6 and 10 showed lower cytotoxicity in the human lung cell lines MRC-5 and A549 at concentrations greater than 50 μM. The effects of compounds 6 and 10 on cell viability were studied in a 3D co-culture model of A549 and MRC-5 treated with lipopolysaccharide (LPS) and observed through confocal microscopy. Compounds 6 and 10 downregulated p65 mRNA expression, resulting in a reduction of pro-inflammatory cytokines, including Interleukin 8 (IL-8) and Monocyte Chemoattractant Protein-1 (MCP-1/CCL2), leading to an anti-inflammatory response through Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathways. Compound 6 showed potential anti-inflammatory activity, downregulating Bcl-2 Associated X gene (BAX), which resulted in inhibition of apoptotic cell death when compared to compound 10. In silico molecular dynamic simulation shed light on how these cinnamoyl-flavonoid hybrid derivatives interact with myeloid differentiation factor 2 (MD-2), which is involved in the inflammatory response. Our findings suggest that cinnamoyl-flavonoid hybrid derivatives show potential as anti-inflammatory drugs and anti-SARS-CoV-2 drugs.

In the present work, we designed and successfully synthesized novel steroid sulfatase (STS) inhibitors based on coumarin, tyramine, triazole, and flavone cores with an additional glutamic acid residue in the structure. The molecular modeling studies revealed that designed derivatives have potential to bind to the molecular target active site, at least theoretically. The biological activity of synthesized compounds was evaluated under a two-step procedure including enzymatic assay and cellular studies using human choriocarcinoma JEG-3 cells. Among the synthesized compounds, the derivative 54E was the most active in both enzymatic and cellular experiments. This result agreed with the molecular modeling data, which indicated that derivative 54E demonstrates the highest affinity to the STS active site. In the enzymatic assay, the remaining STS activity values of 12.97, 17.58, and 20.52 % were observed at 10, 1, and 0.1 μM concentrations of compound 54E, respectively. The IC50 value of 22 nM determined in an experiment with JEG-3 cells for compound 54E was close to the IC50 value determined for the reference STS inhibitor Irosustat (2.7 nM). During the evaluation of the uptake mechanism of the compound 54E, we found that organic anion transporting polypeptides (OATPs) may be responsible for its internalization into the cells. Furthermore, the incubation of zebrafish larvae with the compound 54E revealed no detectable toxic effects in vivo indicating that the compound 54E is a very promising candidate for further preclinical investigations.

Garpedvinin A (1), a novel polycyclic polyprenylated acylphloroglucinol (PPAP) with a bicyclo[4,2,1]nonane core, 13 previously undescribed PPAPs, garpedvinins B-N (2-14) and 6 known analogs (15-20) were isolated from Garcinia pedunculata by various chromatographic methods combined with Global Natural Products Social Molecular Networking. The structures were identified by the analyses of spectral characteristics, computational chemistry calculations and single-crystal X-ray diffraction. A plausible biosynthetic pathway for garpedvinin A was suggested based on the isolated precursor, cambogin. Compounds 2-6, 8, 11, 13, 15-18 and 20 displayed cytotoxic effects on three cancer cell lines, HepG2, A549 and MCF-7. 6 showed the strong inhibitory effect on the proliferation of HepG2 cells in vitro, inducing cell apoptosis in a concentration-dependent manner and blocking the cell cycle at the S phase. Furthermore, 6 affected the expression of apoptosis-related proteins Bax, Bcl2 and pro-Caspase-3.