Current computer-aided drug design最新文献

Introduction: Our group previously reported isatin-based hydrazones (ISB1-ISB6) were further evaluated for their in vitro acetylcholine esterase, butylcholinestrase and cytotoxic effects on cancer cell lines. The compounds successfully suppressed AChE and BChE, with Ki values ranging from 1.06±0.07 to 23.57±1.64 nM for AChE and 15.31±1.28 to 84.41±8.04 nM for BChE. However, the IC50 values of these compounds for AChE and BChE were found to be in the ranges of 1.45-25.51 nM and 16.38-92.90 nM, respectively.

Method: Furthermore, to explore the anti-tumor potential of our newly synthesized compounds, we conducted a cytotoxic MTT assay to assess their impact on two different cancer cell lines: MCF7 and A2780.

Results: Our findings highlight diverse cytotoxic profiles among the compounds. Specifically, ISB2, ISB3, and ISB4 demonstrated potential cytotoxicity in the A2780 cell line, while ISB6 exhibited significant cytotoxicity in the MCF7 cell line. This suggests that these compounds have different effects on cancer cell types, indicating the need for further investigation into their potential applications in cancer therapy.

Conclusion: Finally, molecular docking and dynamic study revealed that lead molecule ISB3 provides stability in the AChE and BChE protein-ligand complex.

Background: The global spread of Strongyloides stercoralis has escalated public health concerns, affecting over 600 million people worldwide. The rise in global migration has heightened the risk of transmission, underscoring the urgent need for effective treatment options.

Objective: This study aimed to investigate ten polyphenolic phytochemicals derived from Mangifera indica as potential alternatives to combat S. stercoralis.

Methods: The efficacy of these compounds was evaluated using computational techniques, including density functional theory (DFT) analysis, molecular docking, adsorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment, and molecular dynamics (MD) simulations.

Results: DFT calculations revealed significant chemical reactivity in compounds such as kaempferol, ellagic acid, quercetin, norathyriol, mangiferin, and ferulic acid. Molecular docking identified mangiferin, quercetin, kaempferol, and norathyriol as top candidates for targeting S. stercoralis. A 200-ns MD simulation of the protein-ligand complex demonstrated the stability and binding behavior of these compounds compared to the reference drug, thiabendazole. ADMET screening confirmed their drug-likeness. Notably, quercetin and mangiferin exhibited strong binding affinities (ΔGbind = -42.35 and -54.57 kcal/mol, respectively), outperforming thiabendazole (ΔGbind = -28.94 kcal/mol).

Conclusion: Quercetin and mangiferin emerge as promising alternatives to thiabendazole, offering favorable chemical reactivity, potent inhibition constants, and strong biological activity for the treatment of S. stercoralis.

Background: An important characteristic of the quality-by-design approach is defining risk, which is a combination of the probability of harm and its severity. During risk assessment, it is essential to determine how the formulation, properties of active ingredients and excipients, and process parameters can potentially affect critical quality attributes or critical process parameters.

Objective: to develop an algorithm and a mathematical model for predicting quality risks in the pharmaceutical development of bisoprolol fumarate tablets with indapamide.

Methods: The software programs "Microsoft Excel 2016" and "Statistica 10.0" (StatSoft, Inc.) were used to predict potential risks and to build a regression model of quality-related risks for bisoprolol fumarate tablets with indapamide.

Results: A mathematical model for predicting the tablet quality risk has been developed, incorporating significant predictors: Carr's index for powder mixtures (Х1), evaluation of the pressing process (Х2), uniformity of tablet weight (Х3), tablets hardness testing (Х4), disintegration time (Х6). Four levels of quality risk are defined: low risk [0.8-1.0], moderate risk [0.6-0.8], high risk [0.4-0.6], and critical risk [0-0.4]. The calculated coefficient of determination of the forecasting model (R2=0.8168) testifies to its high quality.

Conclusion: The developed algorithm and mathematical model for predicting tablet quality risks, proposed for the first time, are highly informative and qualitative. It makes it possible to assess and predict risks related to the quality of tablets, arising from the influence of multiple factors.

Background: The potency content of penicillin serves as a crucial indicator for measuring its pharmacological effects, playing a vital role in quality control and clinical applications. In recent years, with the continuous improvement of production efficiency and quality requirements in the pharmaceutical industry, the need for high-frequency monitoring of drug potency has become increasingly urgent. Infrared spectroscopy, as an emerging research tool, has demonstrated immense potential in the field of drug potency testing.

Objective: The objective of this study is to develop a real-time monitoring model for penicillin potency content utilizing near-infrared (NIR) spectroscopy data. This model aims to enable rapid and accurate detection of potency content during the penicillin production process, ultimately enhancing production efficiency and reducing costs.

Method: During the penicillin production process, NIR spectroscopy data from penicillin samples were scanned and collected to form a comprehensive dataset. Five distinct spectral preprocessing methods were combined with three regression models to construct detection models. By comparing the performance of different combinations, the optimal model configuration was identified.

Results: The optimal model configuration identified in this study integrates the Savitzky-Golay filtering method with ridge regression. Under this optimal model, the coefficient of determination for the test set reached 0.990669, indicating an extremely high degree of agreement between the model's predicted values and the actual measured values. This real-time monitoring model for penicillin potency content can be applied as a rapid and non-destructive monitoring method in factory settings.

Conclusion: This study successfully developed a real-time monitoring model for penicillin potency based on NIR spectroscopy technology. The research findings not only provide strong support for potency monitoring during the penicillin production process but also offer new insights and methodologies for non-destructive testing of other pharmaceuticals and chemicals.

Background: The function of HOXC antisense RNA 1 (HOXC-AS1) in lung adenocarcinoma (LUAD) remains largely unexplored.

Objective: The objective of this research was to examine the relationship between HOXC-AS1 levels and LUAD through both bioinformatics analysis and experimental validation.

Methods: We employed statistical methods and bioinformatics to evaluate the correlation between HOXC-AS1 expression and various clinical features, survival predictors, regulatory mechanisms, and immune cell infiltration in LUAD. The levels of HOXC-AS1 in LUAD cell lines were ascertained through quantitative reverse transcription PCR.

Results: HOXC-AS1 displayed significantly increased expression in individuals with LUAD. There was a significant correlation between high HOXC-AS1 levels and diminished overall survival in LUAD patients, characterized by a hazard ratio of 0.66, a 95% confidence interval of 0.49 to 0.88, and a statistically significant P-value (0.005). An elevated expression of HOXCAS1 was found to be a standalone predictor of poor overall survival in LUAD patients, with a Pvalue of 0.002. HOXC-AS1 was found to be implicated in various pathways, such as neuroactive ligand-receptor interaction and asthma, among others. The study revealed a substantial link between high HOXC-AS1 expression and unfavorable outcomes in LUAD, including poor survival and altered immune cell infiltration. LUAD cell lines exhibited a marked increase in HOXC-AS1 expression compared to the Beas-2B normal lung cell line.

Conclusion: The research indicated a strong association between higher levels of HOXC-AS1 and negative outcomes in LUAD, such as reduced survival rates and the presence of immune cell infiltration. HOXC-AS1 could potentially be utilized as a biomarker to anticipate patient prognosis and their likelihood of responding to immunotherapies in LUAD.

Introduction: The extended IL-1 activity is implicated in autoimmune disorders, such as rheumatoid arthritis, diabetes mellitus, and Parkinson's disease, as well as delayed wound healing. Additionally, it can result in cytokine storms during pathogenic infections.

Methods: The regulation was carried out by Interleukin-1 receptor antagonist (IL-1RA), a key anti-inflammatory molecule. IL-1RA serves as a decoy protein that competes with Interleukin-1 receptors (IL-1RI and IL-1RII) for binding, effectively counteracting the activity of Interleukin- 1 (IL-1). The deficiency was substantiated by commercially available recombinant IL-1RA called Anakinra. The main problem with the existing drug is that it has less pharmacokinetics and reduced binding affinity to its receptor, which requires frequent administration of the drug. To overcome these drawbacks, we have designed a new fusion protein by adding an Fc fragment of Human IgGI fused with IL-1RA using a linker in between, and the design aimed to transport the protein into the N-glycosylation pathway. These characteristic features increase the pharmacokinetics, solubility, and binding efficiency of the protein. As the protein was designed to be expressed in a eukaryotic system, to understand the possibility of the proposed hypothesis, we used machine learning-based AlphaFold2 to model the protein structure and molecular simulation studies to understand the functional integrity of the designed protein.

Results: The in silico results showed that the modeled fusion protein structure has very good binding to its receptor with the support of 21 H bonds and 7 salt bridges and maintained the binding stability over the MD simulations.

Conclusion: These findings support fusion protein's potential as a promising and stable therapeutic candidate.

Background: Thermolabile hemolysin (TLH) is a key virulent protein of Vibrio alginolyticus, known for its hemolytic and phospholipase activities, leading to shrimp vibriosis disease. It has been suggested as a potential therapeutic candidate for vibriosis therapy.

Methods: Computational studies, including molecular docking, toxicity analysis, and molecular dynamics (MD) simulations, were conducted to investigate the inhibition of the phospholipase activity of TLH by phytochemicals from Emblica officinalis.

Results: Out of the twenty-nine compounds, the top three, including Ellagic acid (CID 5281855), Quercetin (CID 5280343), and Kaempferol (CID 5280863), were sorted based on their highest molecular docking scores of -9.2, -8.9, and -8.8, respectively. Subsequently, molecular dynamics (MD) simulations of these selected leads were performed to observe the structural stability of these compounds in the binding sites of TLH protein. The MD simulation outcomes indicated that all three compounds demonstrated superior stability throughout 100 nanoseconds compared to the control compound Resveratrol. The molecular simulation results suggest stable interactions, with average root-mean-square deviation (RMSD) and root-meansquare fluctuation (RMSF) values of 1-2 Å and 0-3 Å. Pharmacokinetic and toxicity analyses were conducted to evaluate the suitability and toxicity of these selected compounds. All top three compounds passed the Lipinski rule, and toxicity criteria.

Conclusion: Therefore, these compounds have the potential to serve as effective therapeutics for controlling Vibrio alginolyticus infection in shrimp.

Background: Acute pharyngitis (AP) is a prevalent ailment. Gynostemma pentaphylla (GP), a traditional Chinese medicine (TCM), may treat AP due to its anti-tumor and anti-inflammatory properties, but this remains unexplored.

Methods: This study utilized the TCMSP and Swiss Target Prediction databases to analyze GP's chemical composition and target proteins. The Genecards database was used to identify targets relevant to AP. A PPI network diagram of drug-disease intersection targets was created using the STRING database, and Cytoscape was utilized to create a network visualization diagram of "GP active components-targets-AP" in order to determine key active components of GP in treating AP. Gene ontology (GO) and biological pathway (KEGG) enrichment analyses were conducted on targets in the David database. Molecular docking verification of key targets and components was performed using AutoDock Vina software. In animal experiments, a rat model of AP was induced by a 15% concentrated ammonia solution, and HE staining was conducted to observe histopathological changes in the rat pharynx after intragastric administration of Houyanqing. ELISA was used to detect expression levels of serum interleukin-1-beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α).

Results: A total of 18 active ingredients were screened from GP, among which Ruvoside _ qt, Rhamnazin, 3 ' -methyleriodictyol, and sitosterol were five key active ingredients. The key targets involved EGFR, STAT3, MAPK3, SRC, AKT1, etc. KEGG enrichment analysis showed that GP mainly acted on Pathways in cancer, P13K-AKT signaling Pathways, JAK-STAT signaling pathways, and other signaling pathways. Molecular docking results showed that four core compounds and five key targets met the energy matching. Animal experiments showed that compared with the normal group, the expression levels of IL-1β, IL-6, and TNF-α in the AP model group were significantly up-regulated (P < 0.05). In addition, compared with the model group, intragastric administration of the dexamethasone group and gypenosides group could alleviate the up-regulation of inflammatory factors in model rats, and the levels of IL-1β, IL-6, and TNF-α were decreased (P < 0.05).

Conclusion: This study predicted the possible targets of GP in the treatment of AP through network pharmacology. The results suggest that gypenosides may inhibit the expression of inflammatory factors by regulating Pathways in cancer, P13K-AKT, and JAK-STAT signaling pathways to treat AP.

Background: Qi-Gui-Jian-Gu decoction (QGJG), as a clinical empirical formula, has clinical benefits in promoting bone formation, but the underlying mechanism for its application in treating fractures has not been investigated.

Methods: The potential therapeutic target and signaling pathway of QGJG for treating fractures were analyzed by network pharmacology. In vitro, we used bone marrow mesenchymal stem cells (MSCs) to evaluate osteogenic differentiation and mineralization by alizarin red staining, quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB), and immunofluorescence staining. In vivo, the 8w male SPF C57BL/6J mouse femoral fracture model was constructed, and the therapeutic effects of QGJG were evaluated.

Results: By network pharmacology analysis, we found that glycogen synthase kinase 3 beta (GSK3β) was a potential therapeutic target of QGJG for treating fractures. The canonical Wnt signaling pathway was selected as the potential molecular mechanism. QGJG was confirmed to upregulate the mRNA levels of alkaline phosphatase (ALP) and bone morphogenetic protein 2 (BMP2), thereby promoting osteogenic differentiation and mineralization. Mechanistically, QGJG inhibited GSK3β while increasing p-Ser9-GSK3β to increase β-catenin protein expression and its nuclear translocation, implying the activation of the canonical Wnt signaling pathway. In vivo, QGJG administration promoted fracture healing, as demonstrated by the up-regulation of OPN and Osx, and accelerated the progression of ossification at 2 and 3 weeks after surgery.

Conclusion: QGJG promotes osteogenic differentiation and fracture healing by activating the canonical Wnt pathway.

Objective: This study aimed to investigate the medicinal properties of SZS before and after processing and provide novel insights into its potential for treating insomnia.

Methods: This study employed the network pharmacology platform to gather information on the chemical composition of SZS, human targets, genes, molecular networks, and pathways associated with insomnia treatment using SZS. Liquid chromatography-tandem mass spectrometry (LC-MS/ MS) was utilized to analyze the chemical profiles of crude SZS, parched SZS, and their combined decoction. The effects of different SZS products on p-chlorophenylalanine-induced insomnia mice were evaluated through pentobarbital-induced sleep tests, behavioral analyses, examination of brain tissue-related mRNA levels, and measurement of plasma neurotransmitters, aiming to explore the sedative and hypnotic effects of various SZS products.

Results: SZS was found to contain a total of 47 genes, including 22 target genes associated with insomnia. These genes may contribute to the sedative and hypnotic effects through 9 related pathways and 69 biological processes. The active components of SZS remained consistent before and after processing. Jujuboside B was found in higher concentrations in crude SZS, while jujuboside A was more abundant in parched SZS. Additionally, SZS exhibited reduced locomotor activity in mice, enhanced the hypnotic effect of pentobarbital sodium, and decreased the levels of acetylcholinesterase, α-1B adrenergic receptor, and solute carrier family 6 member 4 mRNA in the cortex and hippocampus of mice. The levels of acetylcholine, choline acetyltransferase, 5-hydroxyindoleacetic acid, and glutamate in plasma increased, with the hypnotic effect being proportional to the dosage of the drug.

Conclusion: SZS demonstrates sedative and hypnotic effects, potentially mediated by its influence on neurotransmitter levels and related receptors within the central nervous system. There was a slight variation in regulatory capabilities before and after SZS processing, with the combined decoction of crude and parched SZS exhibiting a more pronounced effect, particularly at higher dosages.