Docking Simulations Research Articles

Sulfaquinoxaline-derived Schiff bases: Synthesis, characterization, biological profiling, and computational modeling

Here, six sulfaquinoxaline Schiff bases were synthesized, and various analytical techniques such as FTIR, 1HNMR, and 13CNMR were employed for the characterization. Additionally, in-vitro biological studies were performed, including antibacterial, antifungal, antioxidant, antidiabetic, and anti-inflammatory activities. Computational tools such as molecular docking, DFT, and MD simulations were applied to explore the binding interactions, molecular structure, and chemical reactivity of sulfaquinoxaline SBs. Lastly, in-silico ADMET studies were performed to investigate drug-likeness properties, toxicity, and metabolism of the synthesized SBs. The prepared SBs demonstrated strong antibacterial activity against S. agalactiae and E. coli better than the standard drug, sulfaquinoxaline. The SBs possessed non-significant antioxidant (DPPH assay) and antidiabetic activities (α-amylase and α-glucosidase). All the derivatives depicted moderate anti-inflammatory activity except 6e (IC50 131.95 µg/mL) which presented comparable activity to the standard drug, diclofenac sodium (IC50 127.27 µg/mL). Computational analyses supported the experimental results, especially for compounds 5e and 6e confirming the robust binding affinities and enduring interactions of SBs with the protein target. In-silico drug-likeness analysis and ADMET prediction demonstrated that SBs were drug-like and had a satisfactory ADMET profile.

Effects of Dapagliflozin in Combination with Hydrochlorothiazide on Cardiac Remodeling in Rats with Heart Failure After Myocardial Infarction.

In addition to its antihypertensive and diuretic effects, hydrochlorothiazide also demonstrates additional cardioprotective properties; however, the existence of a synergistic interaction between dapagliflozin and hydrochlorothiazide remains unclear.To establish a rat model of heart failure for investigating the effects and mechanisms of dapagliflozin in combination with hydrochlorothiazide during early intervention, H9c2 cells were cultured to validate their in vitro efficacy. The combination group exhibits a synergistic improvement in hemodynamics, ejection fraction, and a reduction in plasma B-type natriuretic peptide concentration. This combination effectively decreases collagen volume fraction and the expression of collagen I and III, p47phox, p67phox, NF-κB p65, Bax, and caspase-3. The combination group demonstrates a synergistic effect in enhancing cardiac function, attenuating oxidative stress and inflammation. The in vitro effects of the combination were demonstrated in H9c2 cardiomyocytes. In addition, the combination exhibits a more pronounced inhibitory effect on NHE1 expression. The expression of NHE1 in H9c2 cells is inhibited by hydrochlorothiazide, thereby alleviating the consequences of NHE1 overexpression. The results of molecular docking and kinetic simulations indicate a strong binding affinity (-6.1 kcal/mol) between hydrochlorothiazide and NHE1, resulting in the formation of a stable conformation. This may elucidate the underlying mechanism responsible for the synergistic effects of drugs.The combination of dapagliflozin and hydrochlorothiazide has synergistic effects on improving cardiac function, oxidative stress, and inflammation in rats with heart failure. Hydrochlorothiazide binds to and inhibits the expression of NHE1, thereby enhancing dapagliflozin's inhibitory effect on NHE activity. This mechanism potentially elucidates its enhanced cardioprotective effects.

THIOSTREPTON MODULATES TLR4 EXPRESSION AND INDUCES APOPTOSIS IN MDA MB 231 CELLS: AN IN VITRO AND IN SILICO ANALYSIS

Objective: Toll-like receptors (TLRs) are key pattern recognition receptors involved in tumorigenesis, apoptosis, and metastasis. Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with a poor prognosis. Although the role of TLRs in breast cancer remains underexplored, recent studies suggest targeting TLRs in TNBC could be beneficial. In this study Thiostrepton, an antibiotic and novel inhibitor of TLR7-9 in psoriatic inflammation, was investigated for its effects on TLR3, TLR4, and TLR9 expression in TNBC cells (MDA-MB-231). Materials and Methods: The cytotoxicity of thiostrepton was assessed using the MTT assay. RT-PCR was used to measure gene expression levels of TLR3, TLR4, TLR9, Bax, Bcl-2, Nf-κB, and E-cadherin. Cell morphology changes were analyzed with Acridine Orange/Ethidium Bromide (AO/EtBr) staining. Molecular docking and dynamics simulations examined interactions between thiostrepton and the TLR4-MD-2 complex. Results: Thiostrepton led to a concentration- and time-dependent decrease in cell viability. It significantly inhibited TLR4, Bcl-2 gene expression and increased TLR3, Bax, and Nf-κB levels. The changes in Bax and Bcl-2 gene expression, along with alterations in cell morphology, demonstrated that thiostrepton promoted apoptosis in MDA-MB-231 cells. While TLR9 expression reduction was not significant, thiostrepton notably increased TLR3 expression and decreased TLR4 expression. The three independent molecular dynamics simulations demonstrated that thiostrepton binds stably to the TLR4-MD2 domain, exhibiting a high binding affinity as indicated by the binding free energy calculations. Conclusion: Thiostrepton effectively induces apoptosis and reduces cell viability in TNBC cells. In silico analysis suggest thiostrepton could modulate TLR4, highlighting its potential as a candidate for further research and therapeutic development.

Modulation of the LIMK Pathway by Myricetin: A Protective Strategy Against Neurological Impairments in Spinal Cord Injury.

Spinal cord injury (SCI), one of the major disabilities concerning central nervous system injury, results in permanent tissue loss and neurological impairment. The existing therapeutic options for SCI are limited and predominantly consist of chemical compounds. In this study, we delved into the neuroprotective effects of myricetin, a natural flavonoid compound, and the underlying mechanisms, specifically in the context of SCI, utilizing an in vivo model. Previously, our investigations revealed an elevation in the phosphorylated form of Lin-11, Isl-1, and Mec-3 kinase1 (LIMK1) at chronic time points postinjury, coinciding with neuronal loss and scar formation. Our primary objective here was to assess the potential neuroprotective properties of myricetin in SCI and to ascertain if these effects were linked to LIMK inhibition, a hitherto unexamined pathway to date. Computational docking and molecular dynamics simulation studies were performed to assess myricetin's potential to bind with LIMK. Then, using a rat contusion model, SCI was induced and different molecular techniques (Western blot, Evans Blue assay, quantitative reverse transcription polymerase chain reaction and immunohistochemistry) were performed to determine the effects of myricetin. Remarkably, computational docking models identified myricetin as having a better interaction profile with LIMK than standard. Subsequent to myricetin treatment, a significant downregulation in phosphorylated LIMK expression was observed at chronic time points. This reduction correlated with a notable decrease in glial and fibrotic scar formation, and enhanced neuroprotection indicating a positive outcome in vivo. In summary, our findings underscore myricetin's potential as a bioactive compound capable of attenuating SCI-induced injury cascades by targeting the LIMK pathway.

Caffeoylquinic acids from Silphium perfoliatum L. show hepatoprotective effects on cholestatic mice by regulating enterohepatic circulation of bile acids

Ethnopharmacological relevanceThe incidence of cholestatic liver disease (CLD), which is primarily marked by abnormal bile acids (BAs) metabolism and can result in significant hepatic injury, is rising. Nevertheless, there remains a lack of effective treatments and drugs in clinical practice. Silphium perfoliatum L. (SP) is rich in various structural types of caffeoylquinic acid (CQA) compounds, and it is a traditional herb of North American Indians with hepatobiliary therapy effects. However, its therapeutic effect and mechanism of action on CLD have never been studied. Aim of the studyTo determine if SP-8, an extract rich in CQAs from SP, protects against cholestatic liver injury induced by alpha-naphthylisothiocyanate (ANIT) and to clarify its mechanism based on the farnesoid x receptor (FXR) signaling pathway and enterohepatic circulation of BAs. Materials and methodsThe therapeutic efficacy of SP-8 was evaluated by assessing the serum biochemical indices, inflammatory factors, and liver histopathology. Targeted metabolomics of the BAs was studied in the feces, liver, serum, and bile using UPLC-MS/MS. Additionally, a Western blot analysis was used to examine the expression levels of the peroxisome proliferator-activated receptor γ (PPARγ), the FXR, and proteins related to the synthesis and transport of BAs. 16S rRNA gene sequencing was performed to evaluate the gut microbiota (GM). Finally, molecular docking simulations were conducted to assess the interaction between seven types of CQAs from SP-8 with FXR and PPARγ. ResultsSP-8 significantly enhanced the health status of cholestatic mice induced by ANIT as evidenced by a notable reduction in the liver function indices and pro-inflammatory factors, restoration of liver pathological damage, and acceleration of BAs excretion through the feces. In addition, the levels of harmful secondary BAs in the liver and blood were significantly reduced by SP-8. Furthermore, the results of the study on the mechanism of action confirmed that SP-8 not only regulated FXR and PPARγ but also significantly ameliorated the GM structure, thereby promoting the enterohepatic circulation of BAs and achieving the homeostasis of the BAs in the blood and liver. In addition, SP-8 successfully reduced the inflammatory response by strongly suppressing the nuclear translocation of NF-κBp65. According to the molecular docking results, the extract's primary active ingredients could be the seven CQAs in SP-8, as they exhibited a strong affinity for both FXR and PPARγ. Finally, the Mantel test analysis revealed a significant correlation among cholestatic-associated parameters, the GM, and BAs. ConclusionIt was confirmed for the first time that the SP-8 extract of Silphium perfoliatum L. that is rich in seven CQAs had a strong therapeutic effect on ANIT-induced CLD. Its mechanism may involve the regulation of the FXR signaling pathway and the amelioration of the GM structure to promote the homeostasis of BAs enterohepatic circulation. This study provides a potential candidate medicinal herb and its components for the development of CLD therapeutic drugs.

Inhibitory Effect of Phenolic Compounds on Vascular Endothelial Growth Factor-Induced Retinal Endothelial Permeability and Angiogenesis.

Age-related macular degeneration (AMD), often triggered by endothelial barrier disruption through vascular endothelial growth factor (VEGF), is a leading cause of blindness. This study investigated the inhibitory effects of phenolic compounds on VEGF-induced endothelial cell proliferation, migration, angiogenesis, and permeability using human retinal microvascular endothelial cells (hRECs). Thirty-seven polyphenolic compounds were selected from various databases based on their antioxidant properties, abundance in food, and solubility. These compounds significantly reduced migration, tube formation, and endothelial permeability in VEGF-stimulated hRECs. Notably, formononetin, eriodictyol, biochanin A, and p-coumaric acid were more effective in suppressing VEGF-induced angiogenesis and endothelial permeability than lutein. Molecular docking simulations revealed that formononetin, eriodictyol, and biochanin A had relatively lower binding energies with VEGF receptor 2 (VEGFR2) than lutein and sorafenib. These findings highlight the potential of phenolic compounds to be used as VEGFR2 inhibitors and an alternative strategy for preventing AMD.

Molecular Docking Insights into Gatifloxacin Derivatives as Prospective Antidepressant Agents

ABSTRACT: The current focus in drug discovery aims to identify promising therapeutic candidates for further research. Depression, a significant public health issue, is closely linked to low serotonin levels. Researchers are investigating novel antidepressant agents through chemical modifications and protein analysis. The various derivatives are assessed for their antidepressant activity through in silico molecular docking simulations by using AutoDock and ADME analysis. Autodock includes formation of PDBQT files, docking of converted ligands and protein forms, formation of 9 different positions of docked molecules results into binding score, 2D image and 3D images of same one. Docking studies reveal molecular interactions between biological macromolecules (8FSB) and ligands, with strong protein-ligand interactions potentially inhibiting the reuptake of serotonin at the post-synaptic nerve, thereby increasing serotonin availability and exerting antidepressant effects. Gatifloxacin derivatives demonstrated higher binding affinities with 8FSB, Gati I (-11.4 kcal/mol), Gati II (-11.1 kcal/mol), Gati III (-8.2 kcal/mol), Gati IV (-7.9 kcal/mol), Gati V (-9.5 kcal/mol), and Gati VI (-9.7 kcal/mol), all exceeding gatifloxacin (-6.9 kcal/mol). These findings suggest that gatifloxacin derivatives may serve as potent antidepressants of drug discovery lies in the synergistic use of in vitro and in vivo studies, leveraging technological advancements to develop safer and more effective therapies. The findings related to gatifloxacin derivatives highlight the potential of these approaches in identifying novel antidepressants, paving the way for further research and clinical trials.

Determination of Potential Lead Compound from Magnolia officinalis for Alzheimer’s Disease through Pharmacokinetic Prediction, Molecular Docking, Dynamic Simulation, and Experimental Validation

Amyloid β protein (Aβ) deposition has been implicated as the molecular driver of Alzheimer’s disease (AD) progression. The modulation of the formation of abnormal aggregates and their post-translational modification is strongly suggested as the most effective approach to anti-AD. Beta-site APP-cleaving enzyme 1 (BACE1) acts upstream in amyloidogenic processing to generate Aβ, which rapidly aggregates alone or in combination with acetylcholinesterase (AChE) to form fibrils. Accumulated Aβ promotes BACE1 activation via glycogen synthase kinase-3β (GSK-3β) and is post-translationally modified by glutaminyl cyclase (QC), resulting in increased neurotoxicity. A novel multi-target inhibitor as a potential AD agent was identified using an in silico approach and experimental validation. Magnolia officinalis, which showed the best anti-AD activity in our preliminary study, was subjected to analysis, and 82 compounds were studied. Among 23 compounds with drug-likeness, blood–brain barrier penetration, and safety, honokiol emerged as a lead structure for the inhibition of BACE1, AChE, QC, and GSK-3β in docking and molecular dynamics (MD) simulations. Furthermore, honokiol was found to be an excellent multi-target inhibitor of these enzymes with an IC50 of 6–90 μM, even when compared to other natural single-target inhibitors. Taken together, the present study is the first to demonstrate that honokiol acts as a multiple enzyme inhibitor with an excellent pharmacokinetic and safety profile which may provide inhibitory effects in broad-range areas including the overproduction, aggregation, and post-translational modification of Aβ. It also provides insight into novel structural features for the design and discovery of multi-target inhibitors for anti-AD.

Chemical Constituents, Biological Activities and Molecular Docking Studies of Root and Aerial Part Essential Oils from Erigeron sublyratus Roxb. ex DC. (Asteraceae).

In this study, the volatile components of Erigeron sublyratus essential oils and their anti-inflammatory and cytotoxic activities were investigated for the first time. Gas chromatography-mass spectrometry (GC-MS) analysis revealed that a total of 28 components were identified in the root and aerial part essential oils. Among them, cis-lachnophyllum ester (53.4-64.2%), followed by germacrene D (5.6-8.6%), trans-β-ocimene (2.6-7.5%), β-caryophyllene (4.7-6.8%), β-myrcene (2.0-6.3%), and (E)-β-famesene (4.8-5.0%) were principal components. The root essential oil significantly inhibited nitric oxide (NO) production on LPS-induced RAW264.7 cells (IC50 = 1.41 ± 0.10 µg/mL) as compared to standard, dexamethasone (IC50 = 5.43 ± 0.54 µg/mL). Besides, both root and aerial part essential oils exhibited cytotoxic activity against MCF-7, SK-LU-1, and HepG2 (IC50 from 1.11 ± 0.04 to 1.70 ± 0.05 µg/mL). Molecular docking simulation results show that (E)-β-farnesene exhibits the strongest binding energy among the studied compounds with the VEGFR-2 enzyme (ΔG = -7.295 kcal/mol), while δ-cadinene demonstrates the strongest affinity (ΔG = -8.047 kcal/mol) towards the COX-2 enzyme. Furthermore, hydrophobic interactions were indicated to be the main contributors to the binding ability in the studied protein-ligand complex. These findings proposed that E. sublyratus can be exploited for its anti-inflammatory and anti-cytotoxicity potential.

Prominent Neuroprotective Potential of Indole-2-N-methylpropargylamine: High Affinity and Irreversible Inhibition Efficiency towards Monoamine Oxidase B Revealed by Computational Scaffold Analysis

Background: Monoamine oxidases (MAO) are flavoenzymes that metabolize a range of brain neurotransmitters, whose dysregulation is closely associated with the development of various neurological disorders. This is why MAOs have been the central target in pharmacological interventions for neurodegeneration for more than 60 years. Still, existing drugs only address symptoms and not the cause of the disease, which underlines the need to develop more efficient inhibitors without adverse effects. Methods: Our drug design strategy relied on docking 25 organic scaffolds to MAO-B, which were extracted from the ChEMBL20 database with the highest cumulative counts of unique member compounds and bioactivity assays. The most promising candidates were substituted with the inactivating propargylamine group, while further affinity adjustment was made by its N-methylation. A total of 46 propargylamines were submitted to the docking and molecular dynamics simulations, while the best binders underwent mechanistic DFT analysis that confirmed the hydride abstraction mechanism of the covalent inhibition reaction. Results: We identified indole-2-propargylamine 4fH and indole-2-N-methylpropargylamine 4fMe as superior MAO-B binders over the clinical drugs rasagiline and selegiline. DFT calculations highlighted 4fMe as more potent over selegiline, evident in a reduced kinetic requirement (ΔΔG‡ = −2.5 kcal mol−1) and an improved reaction exergonicity (ΔΔGR = −4.3 kcal mol−1), together with its higher binding affinity, consistently determined by docking (ΔΔGBIND = −0.1 kcal mol−1) and MM-PBSA analysis (ΔΔGBIND = −1.5 kcal mol−1). Conclusions: Our findings strongly advocate 4fMe as an excellent drug candidate, whose synthesis and biological evaluation are highly recommended. Also, our results reveal the structural determinants that influenced the affinity and inhibition rates that should cooperate when designing further MAO inhibitors, which are of utmost significance and urgency with the increasing prevalence of brain diseases.

Expression analysis, molecular docking and molecular dynamics simulations to identify potential BTK inhibitors: strategy for targeting pan-cancer

ABSTRACT Bruton's Tyrosine Kinase (BTK), a soluble tyrosine kinase plays an essential role in the growth, development, and signalling of B cells. It is a non-receptor kinase that is crucial for leukemic cell survival, proliferation, and oncogenic signalling in many B cell malignancies. The enhanced metastasis caused by BTK expression may be reduced by BTK inhibitors, which also have powerful therapeutic effects. The goal of the study is to identify potential inhibitors which have good binding affinity with BTK. The current study also aims to investigate the expression pattern and the prognostic significance of BTK across all cancer types. Interestingly, it was found that BTK was highly overexpressed in numerous cancer types including; clear cell renal carcinoma, glioblastoma, head and neck, liver and breast cancer. BTK was found to reduce the relapse-free and overall survival rate. Furthermore, using in silico approach two structural analogues of Pirtobrutinib namely; 163207918 and 129269825 that bind to BTK with higher affinity were identified. Using drug-likeness analysis the therapeutic possibility of screened Pirtobrutinib analogues were evaluated. The Molecular docking and dynamic analysis revealed that the new Pirtobrutinib analogues could be potent inhibitors with higher binding affinity and stability in comparison with the parent compound. In conclusion, after preclinical and clinical research, the identified analogues may open the door for their prospective use in cancer therapy.

Molecular docking and dynamics simulation of farnesol as a potential anticancer agent targeting mTOR pathway.

Farnesol is a natural acyclic sesquiterpene alcohol, found in various essential oils such as, lemon grass, citronella, tuberose, neroli, and musk. It has a molecular mass of 222.372g/mol and chemical formula of C₁₅H₂₆O. The main objective of this study was to assess the effect of farnesol on mTOR and its two downstream effectors, p70S6K and eIF4E, which are implicated in the development of cancer, via molecular dynamic simulation, and docking analysis in an in silico study. A multilayer, primarily computer-based analysis was conducted to assess farnesol's anticancer potential, with a focus on primary cancer targets. From the calculations performed, farnesol showed a binding affinity of - 9.66kcal/mol, followed by binding affinity of - 7.4kcal/mol and - 7.8kcal/mol for mTOR, p70S6K and eIF4E respectively. Rapamycin showed the binding affinity of - 10.45kcal/mol for mTOR, for p70S6K and eIF4E the calculated binding affinity was - 10.65kcal/mol and 8.16kcal/mol respectively. The binding affinity of farnesol was comparable to the standard drug rapamycin indicating its potential as an mTOR inhibitor. Molecular dynamics simulations suggest that the ligands (farnesol and rapamycin) were well trapped within the active site of the protein over a time gap of 50 ns. It is clear that farnesol showed relatively stable MD simulation results, with minor fluctuations and maintains a consistent binding orientation, suggesting a strong and stable interaction with the target proteins when compared to simulation data of standard drug. This study explores the potential of farnesol as an anticancer agent through an in-silico approach, focusing on its interaction with mTOR and its downstream effectors. Inhibition of mTOR signaling pathway may be responsible for the anticancer effect of farnesol. As this pathway plays a crucial role in cell proliferation and survival, making it a significant target in cancer research.

Comparative studies on the interaction of casticin with five digestive enzymes using multi-spectroscopic methods, enzyme activities, and computational simulations

Casticin, which belongs to the flavonoid class, has been studied extensively due to its interesting biological activities. α-Amylase, trypsin, α-chymotrypsin, pepsin and lipase are common digestive enzymes with important physiological functions. In this study, the interactions of casticin with α-amylase, trypsin, α-chymotrypsin, pepsin and lipase were investigated by spectroscopy, enzymology and computational simulations. It has been shown that casticin binds to five digestive enzymes to form casticin-enzyme complexes with weak quenching ability, binding affinity and inhibitory activity. It is elucidated that casticin has different effects on the quenching constants, binding constants, number of binding sites, thermodynamic parameters, conformational microenvironment, secondary structure and binding stability of digestive enzymes. The interactions between casticin and α-amylase, trypsin, α-chymotrypsin, pepsin and lipase are a spontaneous exothermic process driven by enthalpy and entropy, and the binding forces are hydrogen bonds, van der Waals forces and hydrophobic interactions. Computational simulations, including molecular docking and molecular dynamics simulations, were employed to predict the binding model of casticin to these digestive enzymes. In summary, our research provides a theoretical guidance for exploring the role of casticin in pharmacology and biochemistry, which contributes to the understanding of the binding mechanism of casticin to digestive enzymes and its biological activity in vivo.

Nucleic acid binding affinity and antioxidant activity of N-m-Tolyl-4-Chlorophenoxyacetohydroxamicacid.

Hydroxamic acids represent a group of weak organic acids, both naturally occurring and synthetically derived, characterized by the general formula RC(= O)N(R'OH). In this study, we investigated the binding behavior of N-m-tolyl-4-chlorophenoxyaceto hydroxamic acid with calf thymus DNA (ct-DNA) and torula yeast RNA (t-RNA) through a combination of techniques including UV-visible spectroscopy, fluorescence emission analysis, viscometry, and computational simulations using AutoDock4 software. Our findings reveal that the mode of binding between the compound and the nucleic acids is consistent with intercalation. Competitive binding experiments demonstrated that the complex competes effectively with ethidium bromide (EB) for binding to ct-DNA/t-RNA, displacing EB from its binding sites. Additionally, the introduction of the compound into the DNA-EB system resulted in a quenching of fluorescence emission peaks. Analysis of absorption spectra indicated a red shift and hypochromic shift when the compound interacted with DNA, further supporting the intercalative binding mode. The calculated binding constant (Kb) value for the compound is 6.62 × 104M-1 and 5.40 × 103M-1 indicating a strong interaction with ct-DNA and t-RNA respectively. We determined the Stern-Volmer constants for ct-DNA and t-RNA as 9.96 × 104M-1 and 8.13 × 105M-1, respectively. The binding free energy values for ct-DNA/t-RNA were calculated to be -3.741 × 107 and -5.425 × 108kcal/mol, respectively. Viscometric studies corroborated the UV results, showing a continuous increase in relative viscosity of ct-DNA/t-RNA solutions with the addition of the optimal hydroxamic acid concentration. Furthermore, we assessed the antioxidant activity of the compound using DPPH-radical scavenging and β-carotene linoleic acid assays. Gel electrophoresis results demonstrated the compound's remarkable efficacy in preventing DNA damage. Collectively, all experimental evidence supports the conclusion that N-m-tolyl-4-chlorophenoxyaceto hydroxamic acid binds to ct-DNA/t-RNA through an intercalative mechanism, which is consistent with our molecular docking simulations.

Integrative bioinformatic and experimental analysis of benzoylbenzodioxol derivatives: hypoglycemic potential in diabetic mice.

We investigated the hypoglycemic activity and pharmacokinetic study of two synthesized benzoyl benzodioxol derivatives, compound I (methyl 2-(6-(2-bromobenzoyl)benzo[d][1,3]dioxol-5-yl)acetate), and compound II, 2-(6-benzoylbenzo[d][1,3]dioxol-5-yl)acetic acid, which showed very strong α-amylase inhibiting activity in our previous study. Then, diabetes was induced by the injection of streptozotocin to mice. The molecular docking simulations and analyses of density functional theory analyses were conducted to study the binding interactions with human pancreatic alpha-amylase, and their pharmacokinetic properties were further evaluated by ADMET profiling. Compound I showed the most important hypoglycemic effect, decreasing the blood glucose by 32.4%, higher than that of compound II by 14.8% and even the positive control acarbose by 22.9%. Histopathological examination revealed that diabetic livers showed portal inflammation with some apoptotic hepatocytes due to streptozotocin treatment, whereas controls without any treatment maintained normal liver architecture. Molecular docking studies gave results for the best binding affinity of the compound I, through its strong water bridges and π-π interactions, and also through analysis with density functional theory, was more stable and reactive when compared to compound II. Further ADMET analysis showed that both compounds shared a promising pharmacokinetic profile, and compound I had the potential for CNS penetration. Thus, compound I was selected as the best candidate for developing new hypoglycemic agents with potent efficacy, good binding interactions, and excellent pharmacokinetic properties.

Based on green synthesis, multisensory evaluations and molecular simulation approaches: Exploring the taste-enhancing characteristics and mechanisms of N-succinyl-L-leucine

N-Succinyl amino acids (N-Suc-AAs) are increasingly recognized for their potential as taste-active compounds. However, research into the green synthesis, taste-enhancing properties, and mechanisms of N-succinyl-L-leucine (N-Suc-Leu) remains limited. This study employed an enzymatic synthesis method, catalyzed by protamex and pancreatin, to produce N-Suc-Leu, with its structure confirmed. Multiple sensory techniques demonstrated that N-Suc-Leu markedly enhanced the umami, saltiness, and kokumi intensity, and prolonged the duration of umami by 25%. Sigmoid curve analysis further revealed the synergistic enhancement of N-Suc-Leu on the perceptions of umami and saltiness. Molecular docking and dynamics simulations revealed that N-Suc-Leu could bind with T1R1, T1R3, TMC4, and CaSR, enhancing the sensations of saltiness, umami, and kokumi, and bound closely to these receptors without altering their overall conformation. These findings offered a systematic explanation of the potential and mechanism of enzymatically synthesized N-Suc-Leu in enhancing taste and provided novel insights into potential strategies for the development and innovation of taste enhancers and food flavors.

Integrating protein interaction and pathway crosstalk network reveals a promising therapeutic approach for psoriasis through apoptosis induction

Psoriasis is a complex inflammatory skin disease manifested by altered proliferation and differentiation of keratinocytes with dysfunctional apoptosis. This study aimed to identify regulatory factors and comprehend the underlying mechanisms of inefficient apoptosis to open up promising therapeutic approaches. Incorporating human protein interactions, apoptosis proteins, and physical relationships of psoriasis-apoptosis proteins helped us to generate a psoriasis-apoptosis interaction (SAI) network. Subsequently, topological and functional analyses of the SAI network revealed effective proteins, functional modules, hub motifs, dysregulated pathways and transcriptional gene regulatory factors. Network pharmacology, molecular docking and molecular dynamics simulation methods identified the potential drug-target interactions. RELA, MAPK1, MAPK3, MMP9, IL1B, AKT1 and STAT1 were revealed as effective proteins. The MAPK1-MAPK3-RELA motif was identified as a hub regulator in the crosstalk between 41 pathways. Among all pathways, “lipid and atherosclerosis” was found to be the predominant pathway. Acetylcysteine, arsenic-trioxide, β-elemene, bortezomib and curcumin were identified as potential drugs to inhibit pathway crosstalk. Experimental verifications were performed using the literature search, GSE13355 and GSE14905 microarray datasets. Drug-protein-pathway interactions associated with apoptosis were deciphered. These findings highlight the role of hub motif-mediated pathway-pathway crosstalk associated with apoptosis in the complexity of psoriasis and suggest crosstalk inhibition as an effective therapeutic approach.

Phenolic Compositions of Different Fractions from Coffee Silver Skin and Their Antioxidant Activities and Inhibition towards Carbohydrate-Digesting Enzymes.

Seeking food-derived antioxidants and inhibitors of α-glucosidase and α-amylase has been recognized as an effective way for managing diabetes. Coffee silver skin (CSS) is rich in phenolic compounds, which may be potential agents as antioxidants and for α-glucosidase and α-amylase inhibition. But whether phenolics in different forms show similar bioactivity remains unknown. In this study, phenolic compounds in CSS were extracted as free phenolics (FPs), esterified phenolics (EPs), and bound phenolics (BPs). The phenolic profiles and antioxidant activities of them were investigated. Their inhibitory effects on α-glucosidase and α-amylase were analyzed, and the inhibitory mechanisms were elucidated by molecular docking and molecular dynamic simulation. Results showed that FPs exhibited the best antioxidant ability and inhibitory effects on α-glucosidase and α-amylase. A total of 17 compounds were identified in FPs with 3-caffeoylquinic acid, 4-feruloylquinic acid, and dicaffeoylquinic acids as the dominant ones. Typical phenolics in FPs could bind to α-glucosidase and α-amylase through hydrogen bonds and form hydrophobic interaction with several key amino acid residues. In addition, 3,4-dicaffeoylquinic acid and 3-caffeoylquinic acid might be the principal components that account for the inhibitory effect of FPs on α-glucosidase. The results of this study may provide some scientific support for CSS utilization as a health-beneficial component in functional food development for type 2 diabetes mellitus management.

In vitro and in silico characterization of the transport of selected perfluoroalkyl carboxylic acids and perfluoroalkyl sulfonic acids by human organic anion transporter 1 (OAT1), OAT2 and OAT3

Perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkyl sulfonic acids (PFSAs) belong to the group of poly- and perfluoroalkyl substances (PFASs), which may accumulate in humans due to their limited excretion. To provide more insight into the active renal excretion potential of PFASs in humans, this work investigated in vitro the transport of three PFCAs (PFHpA, PFOA, PFNA) and three PFSAs (PFBS, PFHxS and PFOS) using OAT1-, OAT2- or OAT3-transduced human embryonic kidney (HEK) cells. Only PFHpA and PFOA showed clear uptake in OAT1-transduced HEK cells, while no transport was observed for PFASs in OAT2-transduced HEK cells. In OAT3-transduced HEK cells only PFHpA, PFOA, PFNA, and PFHxS showed clear uptake. To study the interaction with the transporters, molecular docking and dynamics simulation were performed for PFHpA and PFHxS, for which a relatively short and long half-life in humans has been reported, respectively. Docking analyses could not always distinguish the in vitro transported from the non-transported PFASs (PFHpA vs. PFHxS), whereas molecular dynamic simulations could, as only a stable interaction of the PFAS with the inner part of transporter mouth was detected for those that were transported in vitro (PFHpA with OAT1, none with OAT2, and PFHpA and PFHxS with OAT3). Altogether, this study presents in vitro and in silico insight with respect to the selected PFASs transport by the human renal secretory transporters OAT1, OAT2, and OAT3, which provides further understanding about the differences between the capability of PFAS congeners to accumulate in humans.

Metabolite Profiling and Identification of Sweet/Bitter Taste Compounds in the Growth of Cyclocarya Paliurus Leaves Using Multiplatform Metabolomics.

Cyclocarya paliurus tea, also known as "sweet tea", an herbal tea with Cyclocarya paliurus leaves as raw material, is famous for its unique nutritional benefits and flavor. However, due to the unique "bittersweet" of Cyclocarya paliurus tea, it is still unable to fully satisfy consumers' high-quality taste experience and satisfaction. Therefore, this study aimed to explore metabolites in Cyclocarya paliurus leaves during their growth period, particularly composition and variation of sweet and bitter taste compounds, by combining multi-platform metabolomics analysis with an electronic tongue system and molecular docking simulation technology. The results indicated that there were significant differences in the contents of total phenols, flavonoids, polysaccharides, and saponins in C. paliurus leaves in different growing months. A total of 575 secondary metabolites were identified as potential active metabolites related to sweet/bitter taste using nontargeted metabolomics based on UHPLC-MS/MS analysis. Moreover, molecular docking technology was utilized to study interactions between the candidate metabolites and the sweet receptors T1R2/T1R3 and the bitter receptors T2R4/T2R14. Six key compounds with high sweetness and low bitterness were successfully identified by using computational simulation analysis, including cis-anethole, gluconic acid, beta-D-Sedoheptulose, asparagine, proline, and citrulline, which may serve as candidates for taste modification in Cyclocarya paliurus leaves. These findings provide a new perspective for understanding the sweet and bitter taste characteristics that contribute to the distinctive sensory quality of Cyclocarya paliurus leaves.