Molecular Docking Research Articles

Validation of TYK2 and exploration of PRSS36 as drug targets for psoriasis using Mendelian randomization

Psoriasis is a chronic inflammatory skin disorder with multiple causes, including genetic and environmental factors. Despite advances in treatment, there remains a need to identify novel therapeutic targets. A Mendelian randomization (MR) analysis was conducted to identify therapeutic targets for psoriasis. Data on cis-expression quantitative trait loci were obtained from the eQTLGen Consortium (n = 31,684). Summary statistics for psoriasis (outcome) were sourced from the GWAS Catalog with a sample size of 484,598, including 5,427 cases and 479,171 controls. Colocalization analysis was used to assess whether psoriasis risk and gene expression were driven by shared single nucleotide polymorphisms. Drug prediction and molecular docking were utilized to validate the pharmacological value of the drug targets. The MR analysis found that 81 drug targets were significantly associated, and two (TYK2 and PRSS36) were supported by colocalization analysis (PP.H4 > 0.80). Phenome-wide association studies did not show any associations with other traits at the gene level. Biologically, these genes were closely related to immune function. Molecular docking revealed strong binding with drugs and proteins, as supported by available structural data. This study validated TYK2 as a drug target for psoriasis, in line with its existing clinical use, including the development of decucravacitinib. PRSS36 is a potential novel target requiring further investigation.

Therapeutic effects of DOX-loaded hydrogel MOF nanocarriers on triple negative breast cancer and derivative design via reinforcement learning

Triple negative breast cancer (TNBC) is one of the most difficult of all types of breast cancer to treat. TNBC is characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The development of effective drugs can help to alleviate the suffering of patients. The novel nickel(II)-based coordination polymer (CP), [Ni2(HL)(O)(H2O)3·H2O] (1) (where H4L=[1,1’:2’,1’’-triphenyl]-3,3’’,4’,5’-tetracarboxylic acid), was synthesized via solvothermal reaction in this study. The overall structure of CP1 was fully identified by SXRD, Fourier transform infrared spectroscopy and elemental analysis. Using advanced chemical synthesis, we developed Hyaluronic Acid/Carboxymethyl Chitosan-CP1@Doxorubicin (HA/CMCS-CP1@DOX), a nanocarrier system encapsulating doxorubicin (DOX), which was thoroughly characterized using Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR), and Thermogravimetric Analysis (TGA). These analyses confirmed the integration of doxorubicin and provided data on the nanocarriers’ stability and structure. In vitro experiments showed that this system significantly downregulated Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) in triple-negative breast cancer cells and inhibited their proliferation. Molecular docking simulations revealed the biological effects of CP1 are derived from its carboxyl groups. Using reinforcement learning, multiple new derivatives were generated from this compound, displaying excellent biological activities. These findings highlight the potential clinical applications and the innovative capacity of this nanocarrier system in drug development.

Exploring the anti-inflammatory potential of phytochemicals against STING::TBK1 pathway

ABSTRACT Viral illnesses frequently cause excessive inflammation in the body, which adds to the severity of symptoms and problems. Understanding and regulating this inflammatory response is critical for successful viral infection management and therapy. It is traditional Ayurvedic understanding to reduce inflammation with formulations of Tulsi, Dalchini, Sunthi, and Krishan mirch. Using computer-aided drug discovery methodologies, this study aims to find phytochemicals that interact with TBK1 and are likely to have this anti-inflammatory effect. Molecular docking results revealed that Oleanolic acid, Astiaticoside A, Cepharadione A, Proanthrocyanidin, and Alpha carotene had binding scores of −8.1 kcal/mol, −7.8 kcal/mol, −6.8 kcal/mol, −6.75 kcal/mol, and −6.8 kcal/mol against TBK1, respectively. 20 ns MD simulations of TBK1 in complex with phytochemicals were performed to evaluate complex stability and protein conformational changes. The simulations showed stable complexes with favourable energy profiles, as evidenced by characteristics such as RMSD, RMSF, Rg, and hydrogen bonding. The MM-PBSA analysis produced precise binding affinity estimates. This work emphasises the potential of these phytochemicals and the need for additional in vitro and in vivo validation.

Mechanism of action of "cistanche deserticola-Polygala" in treating Alzheimer's disease based on network pharmacology methods and molecular docking analysis.

This article used network pharmacology, molecular docking, GEO analysis, and Gene Set Enrichment Analysis to obtain 38 main chemical components and 66 corresponding targets involved in Alzheimer's disease (AD) treatment in "Cistanche deserticola-Polygala". Through further Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes enrichment analysis, we obtained AD signalling pathways, calcium signalling pathways, and other signalling pathways related to the treatment of AD with "Cistanche deserticola-Polygala". Molecular docking showed that most of the core chemical components had good binding ability with the core targets. This article aims to reveal the mechanism of "Cistanche deserticola-Polygala" in treating AD and provide a basis for the treatment of AD with "Cistanche deserticola-Polygala".

Quinoa ameliorates polycystic ovary syndrome via regulating gut microbiota through PI3K/AKT/mTOR pathway and autophagy

BackgroundPolycystic ovary syndrome (PCOS) is a unity of endocrine and metabolic disorders, associated with PI3K/AKT/mTOR, autophagy, and gut microbiota. Quinoa is a valuable food source, which contains rich minerals, unsaturated fatty acids, and has a positive modulating effect on metabolic diseases. However, its effects and potential mechanisms on PCOS have not been reported yet. Therefore, the purpose of this study is to investigate the effect of quinoa on PCOS rats by regulating PI3K/AKT/mTOR, autophagy, and gut microbiota.MethodsTen–week-old female Sprague-Dawley (SD) rats have received letrozole for 24 days for induction of PCOS and subsequently were treated with a quinoa diet for 8 weeks. Vaginal smears were used to analyze the estrous cycle of rats. Hormone and biochemical indexes were analyzed by kit assays and glucometer. The pathological changes of ovary, pancreas, duodenum and colon were observed by HE staining. PI3K, AKT, mTOR and autophagy-related proteins in the ovary and colon were measured by western blot and immunohistochemistry staining. Tight junction proteins in colon were measured by immunohistochemistry staining. 16 s rDNA sequencing was used to detect the changes of intestinal microbiota in rats. Network pharmacology and molecular docking were used to study the possible targets and mechanisms of quinoa on PCOS. Spearman correlation analysis was used to study the relationship between intestinal microbial abundance and hormone levels of PCOS rats at the phylum and genus level.ResultsQuinoa significantly improved estrous cycle and biochemical parameters of PCOS-like rats, and the pathological state of ovary, pancreas, duodenum and colon tissues. Especially, quinoa significantly regulated the expression of PI3K, AKT, mTOR and autophagy-related proteins in the ovary. Quinoa may repair the intestinal barrier by upregulating the expression of tight junction proteins in the colon, and regulate autophagy-related factors in colon. Additionally, quinoa increased the abundance of Lactobacillu, Bacteroides and Oscillospira, and decreased the Firmicutes/Bacteroidetes ratio and the Blautia, and Prevotella, reversing the dysregulation of the gut microbiota. Correlation analysis showed that there is a strong correlation between gut microbiota with significant changes in abundance and hormone related to PCOS.ConclusionOur result indicated that effect of quinoa on PCOS maybe associated with activation of the PI3K/AKT/mTOR signaling pathway, inhibition of autophagy, and regulation of intestinal flora.

Electrochemical aptasensor for 2-amino-2-thiazoline-4-carboxylic acid (ATCA), a metabolite for cyanide poisoning

An alternative biomarker for assessing the cyanide levels in postmortem materials is crucial for investigating acute cyanide intoxication. Herein, an aptamer–ligand biorecognition system with high specificity was developed to detect acute cyanide poisoning via its secondary metabolite, 2-amino-2-thiazoline-4-carboxylic acid (ATCA). Potential aptamers were screened from a random library of 66-base single-stranded DNA using GO-SELEX, with individual aptamers being identified through single-stranded DNA sequencing. Molecular docking was employed to predict the affinity of these aptamers toward ATCA and selected counter-targets; these predictions were confirmed using thermodynamic analysis with an isothermal titration calorimeter. Owing to its label-free biomolecular binding interactions, Apt46 exhibited the highest affinity against ATCA and notable selectivity against structurally similar counter-targets. Thus, an amino-tagged Apt46 binding aptamer was attached to a carbon electrode modified with EDC–NHS-activated graphene oxide. The binding of Apt46 to ATCA was quantified by measuring current changes using differential pulse voltammetry. The aptasensor achieved a detection limit of 0.05 µg/mL and demonstrated suitability for detecting ATCA across various biological matrices, with the high recovery percentages ranging from 92.29 to 114.22%. Overall, the proposed ATCA aptasensor is promising for identifying ATCA metabolites in cases of acute cyanide exposure.

Molecular docking, synthesis and preliminary evaluation of hybrid molecules of benzothiazole cross-linked with hydroxamic acid by certain linkers as HDAC inhibitors

Background Molecular hybridization in drug design is proved to be very successful approach to provide new chemical entities with potential activities and desirable physicochemical properties. Histone deacetylases (HDACs) are involved in controlling the behavior and acetylation of histone and non-histone proteins and their inhibition causes block of cell growth, differentiation, changes in gene expression, and death. Consequently, HDAC inhibitors may lead to anticytotoxic activity. An approach of synthesizing hybrid molecules of benzothiazole cross-linked with hydroxamic acid via an amino acid or aminoalkanoic acid was considered. This approach is expected to optimize the anticytotoxic activity of the proposed compounds. Methods Hybrid molecules of benzothiazole cross-linked with hydroxamic acid (2A-E) were synthesized and their chemical structures were confirmed by spectral analyses (FT-IR, 1H-NMR and 13C-NMR). These were subjected to molecular docking on HDAC8 (PDB ID: 1T69). Computational methods were employed using the SwissADME server to predict the ADME parameters and other physicochemical properties. The cytotoxicity evaluation was performed using MTT colorimetric assay. Results Hybrids (2A-E) recorded lower ΔG (-6.322 to - 9.46) than Vorinostat (SAHA, -5.375). ΔG is an affinity scoring function (kcal/mol) and is employed to rank the candidate poses as the sum of the electrostatic and Van der Waals energies. Benzothiazole cross-linked with hydroxamic acid by a p-aminobenzoic acid (2E) has recorded the lowest docking score of -9.460 and this may refer to the possibility of high inhibitory activity. The hybrids showed no violation from Lipinski’s rule and complied with parameters with low possible passive oral absorption and no penetration into BBB. Hybrid molecules of benzothiazole recorded very interesting results, particularly, 2D and 2E which showed significant and remarkable activity. Conclusions Hybrid molecules of benzothiazole cross-linked with hydroxamic acid recorded very interesting results, particularly, compounds 2D and 2E which showed significant and remarkable activity on lung cancer cell line type A549.

Based on Molecular Docking, Molecular Dynamics Simulation and MM/PB(GB)SA to Study Potential Inhibitorsof PRRSV-Nsp4.

Porcine reproductive and respiratory syndrome (PRRS) is one of the most serious infectious immunosuppressive diseases in the world. The nonstructural protein Nsp4 can be used as an ideal target for anti-PRRSV replication inhibitors. However, little is known about potential inhibitors that target Nsp4 to affect PRRSV replication. The purpose of this study was to screen potential natural inhibitors that affect PRRSV replication by inhibiting Nsp4. Five compounds with strong binding affinity to Nsp4 were selected by structure-based molecular docking method. The complexes of naringin dihydrochalcone (NDC), agathisflavone (AGT), and amentoflavone (AMF) with Nsp4 were stable throughout the molecular dynamics simulation. According to MM/PBSA analysis, the free energies of binding of NDC, AGT, and AMF to Nsp4 were less than-30 Kcal/mol. In conclusion, these three compounds are worthy of further investigation as novel inhibitors of PRRSV. This study provides a theoretical basis for the development of anti-PRRSV natural drugs.

In Silico Analysis of Vitamin D Interactions with Aging Proteins: Docking, Molecular Dynamics, and Solvation Free Energy Studies

Aging is a natural process that is also influenced by some factors like the food someone eats, lifestyle decisions, and impacts on general health. Despite the recognized role of nutrition in modulating the molecular and cellular mechanisms underlying aging, there is a lack of comprehensive exploration into potential interventions that can effectively mitigate these effects. In this study, we investigated the potential anti-aging properties of vitamin D by examining its interactions with key molecular targets involved in aging-related pathways. By using molecular docking and dynamics techniques, we evaluate the interactions and stability of vitamins D2 and D3 with key proteins involved in aging pathways, such as SIRT1, mTOR, AMPK, Klotho, AhR, and MAPK. Our results reveal promising binding affinities between vitamin D and SIRT1 forms, with energy values of −48.33 kJ/mol and −45.94 kJ/mol for vitamins D2 and D3, respectively, in aqueous environments. Moreover, molecular dynamics simulations revealed that the vitamin D3–SIRT1 complex exhibited greater stability compared with the vitamin D2–SIRT1 complex. The study calculated the solvation free energy to compare the solubility of vitamins D2 and D3 in water and various organic solvents. Despite their strong interactions with water, both vitamins exhibited low solubility, primarily due to the high energy cost associated with cavity formation in the aqueous environment. Compared with other solvents, water demonstrated particularly low solubility for both vitamins. This suggested that vitamins D2 and D3 preferred binding to aging receptors over dissolving in bulk aqueous environments, supporting their strong therapeutic interactions with these receptors. These findings shed light on the molecular mechanisms underlying vitamin D’s potential anti-aging effects and lay the groundwork for developing nutraceuticals targeting aging and associated diseases. Understanding these mechanisms holds promise for future interventions aimed at promoting healthy aging and enhancing overall well-being.

Atractylodes Lancea and Its Constituent, Atractylodin, Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease via AMPK Activation.

Metabolic dysfunction-associated steatotic liver disease (MASLD), which encompasses a spectrum of conditions ranging from simple steatosis to hepatocellular carcinoma, is a growing global health concern associated with insulin resistance. Since there are limited treatment options for MASLD, this study investigated the therapeutic potential of Atractylodes lancea, a traditional herbal remedy for digestive disorders in East Asia, and its principal component, atractylodin, in treating MASLD. Following 8 weeks of high-fat diet (HFD) feeding, mice received oral doses of 30, 60, or 120 mg/kg of Atractylodes lancea. In HFD-fed mice, Atractylodes lancea treatment reduced the body weight; serum triglyceride, total cholesterol, and alanine aminotransferase levels; and hepatic lipid content. Furthermore, Atractylodes lancea significantly ameliorated fasting serum glucose, fasting serum insulin, and homeostatic model assessment of insulin resistance levels in response to HFD. Additionally, a glucose tolerance test demonstrated improved glucose homeostasis. Treatment with 5 or 10 mg/kg atractylodin also resulted in anti-obesity, anti-steatosis, and glucose-lowering effects. Atractylodin treatment resulted in the downregulation of key lipogenic genes (Srebf1, Fasn, Scd2, and Dgat2) and the upregulation of genes regulated by peroxisome proliferator-activated receptor-α. Notably, the molecular docking model suggested a robust binding affinity between atractylodin and AMP-activated protein kinase (AMPK). Atractylodin activated AMPK, which contributed to SREBP1c regulation. In conclusion, our results revealed that Atractylodes lancea and atractylodin activated the AMPK signaling pathway, leading to improvements in HFD-induced obesity, fatty liver, and glucose intolerance. This study suggests that the phytochemical, atractylodin, can be a treatment option for MASLD.

Potent α-glucosidase inhibitors with benzimidazole-propionitrile hybridization; synthesis, bioassay and docking study.

Background: Diabetes is characterized by a lack of insulin and insensitivity to insulin. In 2013, the global diabetes population was 382million, with 90% of them having type 2 diabetes (non-insulin-dependent). It is predicted that this number will increase to 592million by 2035.Aim: Here, we aimed to synthesize a series of benzimidazole-based derivatives B1-B32 with α-glucosidase inhibition potential as antidiabetic agents.Methods: Compounds B1-B32 were prepared in three three-step reactions, and the structures were elucidated using spectroscopic methods, namely 1H NMR, 13C NMR, MS and IR. Enzyme inhibition and kinetic study were done using commercial assay kits, and molecular docking study using autodock4.Results: Bioassay data showed that twenty-four out of the thirty-two tested compounds exhibited IC50 values ranging from 44 to 745μM, surpassing the standard molecule, acarbose (IC50: 750μM). it was determined that the best compound, B10, functions as a competitive inhibitor. Additionally, a molecular docking study provided insights into the interactions between the four most promising compounds (B5, B6, B10 and B28) and the active site residues within the enzyme.Conclusion: The tested compounds are interesting α-glucosidase inhibitors, which indicates the benefit of more bioassay studies, especially in vivo studies.

Design, synthesis, and mechanism study of novel tetrahydroisoquinoline derivatives as antifungal agents.

In screening for natural-derived fungicides, a series of 32 novel tetrahydroisoquinoline derivatives were designed and synthesized based on tetrahydroisoquinoline alkaloids. Their structures were verified by 1H NMR, 13C NMR, HRMS, and single X-ray crystal diffraction analysis. Most of the target products exhibited medium to excellent antifungal activity against 6 phytopathogenic fungi in vitro at a concentration of 50mg/L. Interestingly, compounds A13 and A25 with EC50 values of 2.375 and 2.251mg/L against A. alternate were similar to boscalid (EC50 = 1.195mg/L). The in vivo experiments revealed that A13 presented 51.61 and 70.97% protection activities against A. alternate at the dosage of 50 and 100mg/L, respectively, which were equal to that of boscalid (64.52 and 77.42%). SDH enzyme assays and molecular docking studies indicated that compound A13 may act on SDH. In addition, the SEM analysis showed that compound A13 could strongly damage the mycelium morphology. These results revealed that A13 may be a promising lead compound for the development of natural-derived fungicides.

Novel Antioxidant Peptides from Fermented Whey Protein by Lactobacillus rhamnosus B2-1: Separation and Identification by in Vitro and in Silico Approaches.

Whey is a byproduct of the dairy industry and is rich in protein. To enhance the significance of such byproducts and find efficacious antioxidants for combating oxidative stress, this study reported on the preparation, purification, and identification of novel peptides with antioxidant activities from whey protein metabolites following fermentation by Lactobacillus rhamnosus B2-1. The isolation and identification processes involved macroporous adsorption resin column chromatography, gel filtration column chromatography, and liquid chromatography-tandem mass spectrometry. Therein, three novel antioxidant peptides (PKYPVEPF, LEASPEVI, and YPFPGPIHNS) were selected to be synthesized, and they demonstrated remarkable antioxidant activities in vitro chemical assays. PKYPVEPF, LEASPEVI, and YPFPGPIHNS (100 μg/mL) displayed a notable cytoprotective impact on HepG2 cells under oxidative stress induced by H2O2, increasing the cell viability from 49.02 ± 3.05% to 88.59 ± 10.49%, 82.38 ± 19.16%, and 85.15 ± 7.19%, respectively. Moreover, the peptides boosted the activities of catalase and superoxide dismutase in damaged cells and reduced reactive oxygen species levels. The molecular docking studies highlighted that these antioxidant peptides efficiently bound to key amino acids in the Kelch domain of Keap1, thereby preventing the interaction between Keap1 and Nrf2. In conclusion, PKYPVEPF, LEASPEVI, and YPFPGPIHNS demonstrated substantial antioxidant activity, suggesting their potential for widespread application as functional food additives and ingredients.

Acetamiprid elicits oxidative stress, pro-inflammatory response, and cellular proliferation in human bronchial epithelial cells in vitro and in silico: alleviative implications of the mixture of heat-killed Lactobacillus strains

BackgroundAcetamiprid (ACE), a neonicotinoid insecticide, has been extensively used to control pests in agricultural and industrial environments. It has been reported that ACE is detrimental to the lungs. Nevertheless, the extent to which the activation of oxidative stress, inflammation, and cellular proliferation contributes to the pulmonary toxicity induced by ACE exposure remains insufficiently understood. This study explored the mechanism of toxicological consequences after ACE exposure in bronchial epithelial cells (BEAS-2B cells). The research also examined the potential ameliorative effects of the mixture of heat-killed Lactobacillus delbrueckii and Lactobacillus fermentum (HKL) on the toxicities of ACE.ResultsFollowing 14 days of exposure to ACE at 0.5 and 1 μM, oxidative stress was induced, as evidenced by the decreased levels of reduced glutathione, catalase, glutathione peroxidase, and superoxide dismutase, along with increased levels of malondialdehyde. Also, ACE exposure results in overexpression and raised protein levels of the IL-25, NF-κB1, NF-κB2, IL-33, TSLP, and NF-κB target genes, which induce inflammatory responses. In addition, ACE boosted Ki-67-positive BEAS-2B cells. The molecular docking of ACE with target genes and their proteins demonstrated a potent binding affinity, further supported by the presence of hydrophobic contacts, electrostatic interactions, and hydrogen bonds. The post-treatment of HKL following the ACE (1 μM) exhibited its antioxidant, anti-inflammatory, and antiproliferative activities in suppressing ACE-induced toxicity.ConclusionsOur research revealed that ACE toxicity in BEAS-2B cells is caused by driving oxidative stress, pro-inflammatory response, and cellular proliferation. This study would give us a strategy to alleviate ACE-induced lung impairment by heat-killed probiotic supplements. As a result, dietary supplements that contain these microorganisms may potentially be beneficial in countries with high levels of pesticide contamination.

Empagliflozin ameliorates olfactory bulbectomy-induced depression by mitigating oxidative stress and possible involvement of brain derived neurotrophic factor in diabetic rats

Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has recently reported to prevent the depression as chronic animal model. However, its impact on neuroinflammation-mediated depression were remains unexplored. The present study aimed to explore the antidepressant potential of empagliflozin using a neuroinflammation-mediated depression involving the olfactory bulbectomy (OBX) model in rats. To establish this model, initially a low dose of streptozotocin was injected to induce diabetes in all group of animals. Following the confirmation of hyperglycemia, OBX surgery was performed. Post-surgery, the drug treatments were administered orally for 14 consecutive days. The study evaluated the effects of daily oral administration of empagliflozin at doses of 5 and 10 mg/kg, alongside metformin (200 mg/kg) and clomipramine (50 mg/kg), on OBX-induced behavioral depression in rats. Separate sham and vehicle control groups were also maintained. Behavioral parameters in open field, forced swim test, elevated plus maze and splash test were recorded on 28th day. Results showed that empagliflozin, particularly at the higher at the higher dose, significantly enhanced behavioral outcomes, evidenced by increased distance traveled, greater open arm entries, and reduced immobility, alongside a notable reduction in grooming time. Moreover, empagliflozin significantly restored the antioxidants level specifically Glutathione (GSH) and Catalase (CAT) in OBX insulted rat brain and reversed Lipid peroxidase (LPO). Notably, molecular docking study demonstrated a good binding affinity of empagliflozin for Brain-Derived Neurotrophic Factor (BDNF), suggesting that its antidepressant effects may be mediated through the modulation of the BDNF pathway. These findings support the potential therapeutic application of empagliflozin for depression, particularly in cases associated with neuroinflammation and oxidative stress.

Antifungal Efficacy of Ultrashort β-Peptides against Candida Species: Mechanistic Understanding and Therapeutic Implications.

Candidiasis, a condition spurred by the unchecked proliferation of Candida species, poses a formidable global health threat, particularly in immunocompromised individuals. The emergence of drug-resistant strains complicates management strategies, necessitating novel therapeutic avenues. Antimicrobial peptides (AMPs) have garnered attention for their potent antifungal properties and broad-spectrum activity against Candida species. This study assessed the antifungal effectiveness of ultrashort β-peptides against Candida strains, with a specific focus on peptide P3 (LAU-β3,3-Pip-β2,2-Ac6c-PEA). Our findings showed P3's remarkable fungistatic and fungicidal activities against Candida albicans, exhibiting an MIC of 4 μg/mL, comparable to those of standard antifungal drugs. The MIC value remained unchanged in the presence of ADC and BSA, indicating that serum albumin does not diminish the activity of P3. P3 demonstrates synergistic effects when combined with Fluconazole (FLU), Itraconazole (ITR), and Nystatin (NYS) to the extent that it becomes effective at 0.125, 0.125, and 0.03125 μg/mL, respectively. Concentration versus time-kill kinetics showed its time-dependent activity up to the first 12 h against C. albicans, and later concentration also played a role; indeed, at 24 h the whole culture was sterilized at 8× MIC. Post-antifungal effect assays confirmed prolonged suppression of pathogen growth after the removal of P3 from the media for significant durations. More importantly, P3 inhibits hyphae formation and biofilm development of Candida, outperforming Fluconazole with respect to these properties. Mechanistic insights display P3's potential to disrupt fungal cell membrane integrity and dose-dependent inhibition of ergosterol biosynthesis, essential for fungal cell wall integrity. Using the Bradford assay, it was observed that extracellular protein concentrations increased with higher doses of the compound, thereby validating the effect of P3 on membrane integrity. A comparative gene analysis using RT-PCR showed that P3 downregulates ERG3, ERG11, and HWP1, which are crucial for the survival and pathogenicity of C. albicans. The impact of P3 on ERG11 and ERG3 is more effective than that of Fluconazole. Molecular docking studies revealed strong binding of P3 to various isoforms of lanosterol 14-α-demethylase, a key enzyme in ergosterol synthesis. Furthermore, molecular dynamic simulations validated the stability of the most promising docking complex. Overall, our findings underscore P3's potential as a leading candidate for the development of innovative antifungal therapies, warranting further investigation and optimization.

Deciphering Cathepsin K inhibitors: a combined QSAR, docking and MD simulation based machine learning approaches for drug design

ABSTRACT Cathepsin K (CatK), a lysosomal cysteine protease, contributes to skeletal abnormalities, heart diseases, lung inflammation, and central nervous system and immune disorders. Currently, CatK inhibitors are associated with severe adverse effects, therefore limiting their clinical utility. This study focuses on exploring quantitative structure–activity relationships (QSAR) on a dataset of CatK inhibitors (1804) compiled from the ChEMBL database to predict the inhibitory activities. After data cleaning and pre-processing, a total of 1568 structures were selected for exploratory data analysis which revealed physicochemical properties, distributions and statistical significance between the two groups of inhibitors. PubChem fingerprinting with 11 different machine-learning classification models was computed. The comparative analysis showed the ET model performed well with accuracy values for the training set (0.999), cross-validation (0.970) and test set (0.977) in line with OECD guidelines. Moreover, to gain structural insights on the origin of CatK inhibition, 15 diverse molecules were selected for molecular docking. The CatK inhibitors (1 and 2) exhibited strong binding energies of −8.3 and −7.2 kcal/mol, respectively. MD simulation (300 ns) showed strong structural stability, flexibility and interactions in selected complexes. This synergy between QSAR, docking, MD simulation and machine learning models strengthen our evidence for developing novel and resilient CatK inhibitors.

Synthesis, α-Glucosidase, α-Amylase, and Aldol Reductase Inhibitory Activity with Molecular Docking Study of Novel Imidazo[1,2-a]pyridine Derivatives

Synthesis, α-Glucosidase, α-Amylase, and Aldol Reductase Inhibitory Activity with Molecular Docking Study of Novel Imidazo[1,2-<i>a</i>]pyridine Derivatives

Evaluation of antiviral efficacy of graphene oxide nanosheets on dengue virus-infected Vero cells: in-vitro and in-silico approaches

Emerging viral diseases have led to an increased demand for novel therapeutic medicines. Graphene nanostructures exhibit excellent inhibitory antiviral effects owing to their unique physic-chemical properties. In this study we have investigated the potential of graphene oxide (GO) nanostructures for antiviral activity. GO was synthesized by Modified Hummer’s method and fully characterized using several chemical-physical techniques to confirm the structure, morphology, optical properties, chemical composition and oxidation states. The antiviral property of the GO was investigated against serotype-2 dengue virus. The results suggest that the antiviral action is attributed to the negative charge of the graphene sheets due to the presence of oxygenated functional groups. Dengue virus −2 infection was suppressed by 90% with GO in a dose-dependent manner. Cytotoxic features of GO against Vero cells were observed when treated at higher concentrations (>75 μg ml−1 IC 50 concentration). The in-silico investigation showed that the interaction between GO nanosheets and serotype-2 dengue virus occurred within the ligand-protein complex as confirmed by molecular docking studies. These results emphasize that GO has strong antiviral activity against serotype-2 dengue virus.

Cimicifuga heracleifolia Kom. attenuates ulcerative colitis through the PI3K/AKT/NF-κB signaling pathway

Ethnopharmacological relevanceCimicifuga heracleifolia Kom. (C. heracleifolia) has demonstrated efficacy in treating gastrointestinal disorders, including splenasthenic diarrhea. Ulcerative colitis (UC), a chronic inflammatory bowel disease, shares similarities with splenasthenic diarrhea. However, the pharmacological effects of C. heracleifolia on UC and the underlying mechanisms remain unexplored.Aim of the study: The present study investigates the therapeutic potential and mechanisms of C. heracleifolia in UC. MethodsInitially, network pharmacology analysis, encompassing ingredient screening, target prediction, protein-protein interaction (PPI) network analysis, and enrichment analysis, was employed to predict the mechanisms of C. heracleifolia. The findings were further validated using transcriptomics and functional assays in a dextran sulfate sodium (DSS)-induced UC model. Additionally, bioactive compounds were identified through surface plasmon resonance (SPR) analysis, molecular docking, and cell-based assays. ResultsA total of 52 ingredients of C. heracleifolia were screened, and 32 key targets were identified within a PPI network comprising 285 potential therapeutic targets. Enrichment analysis indicated that the anti-UC effects of C. heracleifolia are mediated through immune response modulation and the inhibition of inflammatory signaling pathways. In vivo experiments showed that C. heracleifolia mitigated histological damage in the colon, reduced the expression of phosphorylated Akt1, nuclear factor-kappa B (NF-κB) p65, and inhibitor of Kappa B kinase α/β (IKKα/β), suppressed the content of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and enhanced the expression of tight junction proteins. Moreover, cimigenoside, caffeic acid, and methyl caffeate were identified as the bioactive constituents responsible for the UC treatment effects of C. heracleifolia. ConclusionsIn summary, this study is the first to demonstrate that C. heracleifolia exerts therapeutic effects on UC by enhancing the intestinal mucosal barrier and inhibiting the phosphatidylinositol 3-kinase (PI3K)/AKT/NF-κB signaling pathway. These findings offer valuable insights into the clinical application of C. heracleifolia for UC management.