Current computer-aided drug design最新文献

Introduction: The white water lily (Nymphaea alba) is a traditional medicinal plant recognized for its diverse array of bioactive properties. However, its potential in wound healing remains largely unexplored. This study aimed to evaluate the phytochemical profile, cytotoxicity, and wound healing efficacy of Nymphaea alba flower extract (NAFE) using both in vitro and in vivo models, as well as computational network analysis.

Methods: Qualitative phytochemical screening of NAFE was conducted using standard techniques. Cytotoxicity was assessed on HaCaT keratinocyte cells at concentrations ranging from 0 to 1000 μg/ml. In vivo wound healing was evaluated using excision wound models in Wistar albino rats treated with 2.5% and 5% NAFE ointments, measuring wound contraction, epithelialization time, and breaking strength. In vitro scratch assays were used to assess cell migration at selected concentrations of NAFE. A wound-healing-associated network analysis was performed using IMPPAT, STRING, GeneCards, and OMIM databases to explore the molecular targets and interactions of bioactive compounds.

Results: Phytochemical analysis confirmed the presence of alkaloids, flavonoids, phenolics, tannins, and glycosides. NAFE was found to be non-cytotoxic with an IC50 of 245 μg/ml. In vivo, 5% NAFE ointment showed 98.92% wound closure by day 14 and complete closure by day 21, comparable to betadine. Epithelialization time (15.83±0.16 days) was nearly equivalent to the standard drug. In vitro assays demonstrated enhanced HaCaT cell migration at concentrations of 122.5 and 245 μg/ml. Network analysis identified kaempferol and quercetin as key compounds interacting with wound-healing proteins, notably AKT1, ESR1, and EGFR.

Discussion: The findings suggest that NAFE promotes wound healing by enhancing wound contraction, epithelialization, and cell migration, likely through the modulation of molecular pathways involved in tissue repair. The presence of bioactive compounds such as kaempferol and quercetin underpins the extract's pharmacological potential.

Conclusion: Nymphaea alba flower extract exhibits promising wound-healing activity through multiple mechanisms, including enhancement of cell migration and regulation of key proteins involved in tissue regeneration. These results support its potential as a natural therapeutic agent in wound management.

Background: Banxia Xiexin Decoction (BXD) has been shown to exert therapeutic effects on Functional dyspepsia (FD). This study aims to investigate the therapeutic mechanisms of BXD in treating FD.

Methods: Network pharmacology was employed to explore the potential targets of BXD in the treatment of FD. Immunoinfiltration analysis assessed immune activation in FD, with the XGBoost machine learning algorithm used to predict the feature importance of key targets. Deep learning and molecular docking were employed to assess the interactions between active compounds and key targets. Finally, an FD mouse model was established, and Western blotting, immunofluorescence, immunohistochemistry, and Enzyme-linked immunosorbent assay were conducted to validate the findings.

Results: Through network pharmacology analysis and machine learning predictions, three key active compounds were identified. GO enrichment analysis indicated that the mechanism of BXD primarily involves biological processes related to inflammatory responses. Immunoinfiltration analysis suggested that immune activation in FD may be associated with increased mast cell presence. Seven hub genes were identified through PPI analysis, with STAT3 identified as a key feature in XGBoost predictions of FD. In vivo experiments showed that BXD inhibited p- STAT3, alleviated mast cell infiltration and mucosal barrier damage, and enhanced gastrointestinal motility.

Conclusion: BXD may alleviate mast cell infiltration and mucosal barrier damage in FD by inhibiting the expression of p-STAT3, thereby exerting its therapeutic effects.

Introduction: Ovarian cystadenoma (OC) is a common benign tumor in women. Wang's formula for gynecological masses (WGM), a patented traditional Chinese medicine, was reported to have therapeutic potential for OC.

Method: Here, we explored the pharmacological effects of WGM on treating OC via network pharmacology, molecular docking, and molecular dynamics simulations. The active ingredients in WGM and their putative targets were acquired from the TCMSP and BATMAN-TCM platforms. The known therapeutic targets of OC were obtained from the DrugBank, OMIM, and GeneCards databases. GO and KEGG analyses of the overlapping targets were performed via the DAVID database. Molecular docking and molecular dynamics (MD) simulations were conducted to evaluate the binding efficacy of the chemical ingredients to the core targets.

Results: In total, 287 chemicals in WGM may relieve OC by targeting 134 genes involved in malignant tumors, endocrine resistance, and oxidative stress, of which ERBB2, ESR1, and AKT1 play vital roles. Molecular docking revealed stable binding energies of the receptors to the ligands, which bond via electrostatic interactions and van der Waals interactions in MD simulations.

Conclusions: The in silico bioinformatics analysis revealed the mechanisms of WGM treatment for OC. More pharmacological evidence of WGM treatment for OC, such as in vivo and clinical studies, is needed before WGM can benefit more patients.

Introduction: Microalgae, with their high photosynthetic efficiency and sustainability, hold promise to produce bioactive compounds, chemicals, cosmetics, and biofuels. This study aims to understand the molecular mechanisms of bioactive compounds from microalgae using integrative bioinformatics approaches to identify their potential therapeutic applications.

Methods: Gene expression profiles from the GSE113144 and GSE115827 datasets were retrieved from the GEO database using keywords such as liver disease, microalgae, and bioactive compounds. Different expressed genes (DEGs) were identified using the GEO2R tool. Subsequently, a PPI network was constructed to identify hub genes and key regulatory elements. The findings were further cross-validated using a range of bioinformatics tools, databases, and literature to explore their potential applications in drug development, nutraceuticals, and disease modulation.

Results: Following oxo-fatty acid treatment, 2051 differentially expressed genes (DEGs) were identified, while 399 DEGs were detected after sea spray aerosol treatment, with 39 genes shared between the two treatments. These DEGs were primarily enriched in immune and metabolic processes. Protein-protein interaction analysis revealed ten key hub genes: PBK, CENPA, ASPM, DLGAP5, DEPDC1, SPC25, CDCA3, HJURP, ERCC6L, and KIF18B, which are involved in immune and metabolic responses. Functional enrichment highlighted roles in cholesterol and fatty-acyl-CoA binding, peptidoglycan recognition, metal ion binding, and protease activity. Notably, PBK and CDCA3 are associated with approved drugs, suggesting potential for therapeutic repurposing.

Discussion: The molecular functions enriched among hub genes, such as cholesterol binding, fatty-acyl-CoA binding, peptidoglycan receptor activity, and metal ion binding, suggest actionable pathways that could be pharmacologically modulated. These targets are highly relevant to diseases such as NAFLD and chronic inflammation. The identification of druggable hub genes and enriched immune-metabolic functions provides a foundation for further preclinical and translational research.

Conclusion: This study offers valuable insights into the molecular mechanisms underlying human immune and metabolic responses to sea spray aerosols and oxo-fatty acids, identifying cellular pathways and processes that are often regulated in human immune and metabolic responses to various microalgae. Overall, this study enhances our understanding of the potential therapeutic applications of microalgae-derived bioactive compounds, offering potential breakthroughs in drug discovery and nutraceutical development.

Introduction: Xiaoqinglong Decoction (XQLD) is a traditional Chinese medicinal formula commonly used to treat chronic urticaria (CU). However, its underlying therapeutic mechanisms remain incompletely characterized. This study employed an integrated approach combining network pharmacology, bioinformatics, molecular docking, and molecular dynamics simulations to identify the active components, potential targets, and related signaling pathways involved in XQLD's therapeutic action against CU, thereby providing a mechanistic foundation for its clinical application.

Methods: The active components of XQLD and their corresponding targets were identified using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. CU-related targets were retrieved from the OMIM and GeneCards databases. Subsequently, core components and targets were determined via protein-protein interaction (PPI) network analysis and component-target-pathway network construction. Topological analyses were performed using Cytoscape software to prioritize core nodes within these networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted via the DAVID database to identify enriched biological processes and signaling pathways. Molecular docking was performed to evaluate binding interactions between key components and core targets, while molecular dynamics (MD) simulations were employed to assess the stability of the component-target complexes with the lowest binding energy. Finally, CU-related targets of XQLD were validated using datasets from the Gene Expression Omnibus (GEO) database.

Results: A total of 135 active components and 249 potential targets of XQLD were identified, alongside 1,711 CU-related targets. Core components, such as quercetin, kaempferol, beta-sitosterol, naringenin, stigmasterol, and luteolin, exhibited high degree values in the constructed networks. The core targets identified included AKT1, TNF, IL6, TP53, PTGS2, CASP3, BCL2, ESR1, PPARG, and MAPK3. GO and KEGG pathway enrichment analyses revealed the PI3K-Akt signaling pathway as a central regulatory mechanism. Molecular docking studies demonstrated strong binding affinities between active components and core targets, with the stigmasterol-AKT1 complex exhibiting the lowest binding energy (-11.4 kcal/mol) and high stability in MD simulations. Validation using GEO datasets identified 12 core genes shared between CU-related targets and XQLD-associated targets, including PTGS2 and IL6, which were also prioritized as core targets in the network pharmacology analyses.

Discussion: This study comprehensively integrates multidisciplinary approaches to clarify the potential molecular mechanisms of XQLD in treating CU, highlighting its multitarget and multipathway synergistic effects. Molecular docking and dynamics simulations confirm the stable interaction b

Introduction: Excessive phosphorylation of tau protein by the tau-tubulin kinase 1 (TTBK1) enzyme is implicated in the pathogenesis of several neurodegenerative diseases. Based on a comprehensive literature review and availability of the co-crystal structure of TTBK1 in complex inhibitor (pdb id 4BTK), we designed a multiscale computational approach to identify novel hits from the ZINC13 chemical library.

Methods: The High-Throughput Virtual Screening (HTVS) of the ZINC13 database (containing 13,195,609 molecules) was carried out against TTBK1 protein (PDB id 4BTK). Top-scoring molecules and reference molecules were further subjected to MD simulations, PCA analysis, DCCM assay, binding free energies calculations, and in-silico ADME calculations.

Results: From a preliminary HTVS study, six molecules were identified based on their docking scores: ZINC37289024, ZINC89755080, ZINC20993115, ZINC72445968, ZINC28247630, and ZINC16638515, with the docking score of -10.186, -09.229, -09.045, -09.021, -08.920 and -08.821, respectively. In subsequent MD simulations studies, the protein backbone RMSD values were observed to be 1.978, 1.8178, 2.2309, 1.7933, 1.8837, 1.9461, and 1.8711 Å, respectively. Similarly, the protein backbone RMSF values were 0.9511, 1.0172, 1.2023, 1.0591, 1.0029, 1.9755, and 0.9200 Å, respectively. PCA, DCCM, and MMGBSA analysis indicated that these complexes were quite stable throughout the 100 ns MD simulations. In-silico ADME predictions of identified top six hits suggested that these top six hits possess favorable drug-like properties, supporting their potential as the lead candidates for therapeutic development.

Conclusion: A multiscale molecular modelling approach was employed, and six top-scoring hits were identified as promising TTBK1 inhibitors. Analysis of the in-silico data suggested that ZINC37289024 would be the most promising clinical candidate for AD. However, further in-vitro and in-vivo experimental data would be needed for validation of these results.

Background: Since the commencement of the COVID-19 pandemic, researchers have been earnestly exploring the capacity of diverse bioactive compounds present in plants to impede the transmission of SARS-CoV-2. Plants have always held a special place in scientific research as invaluable bio-factories capable of producing a diverse array of chemical compounds with promising therapeutic applications. Cichorium intybus is among these plants, known for its rich reservoir of bioactive phytoconstituents with significant potential for variable health benefits.

Objective: The current work aims to investigate the antiviral activity of various phytoconstituents against SARS-CoV-2 by inhibiting the main protease (Mpro) (PDB code: 6LU7) and spike (S) glycoprotein receptor binding domain (RBD) to Angiotensin-converting enzyme 2 (ACE2) (PDB code: 6M0J) of SARS-CoV-2 and Omicron main protease (PDB code: 7TOB).

Methods: Auto Dock Vina was employed as the docking engine for the evaluation and determination of docking scores. To test whether a chemical satisfies the requirements for an active drug taken orally in humans, the rule of five (Ro5) was calculated. By choosing the proteinligand complex geometry having the highest affinities (highest negative Gibbs' free energy of binding/G), the docking score was calculated. The FDA-recommended antimalarial medications chloroquine and hydroxychloroquine sulfate, Remdesivir, and the antiviral medication nelfinavir were utilized as comparisons.

Results: The results demonstrate that as spike glycoprotein inhibitors, crepidiaside B, 3,5-Dicaffeoylquinic acid, 4,5 -Dicaffeoylquinic acid, and crepidiside A performed better than nelfinavir, chloroquine, hydroxychloroquine sulfate, and remdesivir. The sequence of chemical reactivity of the chosen bioactive phytoconstituents, as determined by quantum chemical DFT calculations, was Crepidiside A

Conclusion: The current investigation discovered bioactive phytoconstituents derived from plants that have the potential to be developed as therapeutic alternatives for COVID-19.

Background: Inflammation is a natural process; however, chronic inflammation may result in numerous health issues. Etoricoxib (ETX), a selective cyclooxygenase-2 (COX-2) inhibitor, serves as an anti-inflammatory agent for various types of arthritis. However, prolonged use of ETX is associated with several adverse effects, including cardiovascular toxicity.

Objective: The current research aims to design an analogue of ETX having superior pharmacokinetic properties and safer toxicological profiles employing the bioisosteric approach.

Methods: The bioisosteres of various groups in ETX were produced utilizing the MolOpt online tool, resulting in the generation of novel ETX analogues. The pharmacokinetics (ADME) and toxicological profiles of the generated analogues were calculated by ADMETLab 3.0 server. The druglikeness (DL) and drugscore (DS) were calculated using OSIRIS property explorer (PEO). The molecular docking analysis of the ETX analogues against the target protein (PDB ID: 5KIR) was carried out using AutoDock Vina, and their results were visualized by Discovery Studio 2021. Molecular Dynamics (MD) simulation of the top three complexes was conducted using the Schrödinger suite. Binding free energy for the A098-5KIR, A188-5KIR, and D121- 5KIR complexes was conducted using MM-GBSA/PBSA method.

Results: A total of 1200 ETX bioisosteres were produced; among them, 51 were screened on the basis of ADMET profile, DL, and DS scores and selected for the docking study. A docking study revealed that 12 analogues show good interactions and docking scores. Furthermore, the molecular dynamics simulation of ligands A098, A188, and D121 demonstrated stability throughout the 100 ns simulation period.

Conclusion: The findings of the ADMET study, DL, DS, docking study, MD simulation, and binding free energy calculation indicate that the analogues A098, A188, and D121, which are bioisosteres of ETX, may serve as potential anti-inflammatory agents for inflammation-related disorders.

Background: Radiation Dermatitis (RD) is a common complication of radiation therapy, with approximately 90% of patients experiencing moderate to severe radiation dermatitis injury after radiotherapy. Jiedu Shengji oil (JDSJY) is a commonly used herbal topical preparation in our hospital, with remarkable clinical efficacy in treating radiation dermatitis. However, the mechanism of JDSJY in treating RD is unclear.

Aims: The aim of the study is to explore JDSJY's mechanism of action in treating RD through methods, such as network pharmacology and in vivo experiments.

Methods: The active components and disease targets of JDSJY were screened and intersected via network pharmacology for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The pharmacodynamics of JDSJY was evaluated by establishing a rat model of RD.

Results: Network pharmacology showed that the pathway network of JDSJY action involved 64 targets and 6 pathways and might act by targeting key targets, such as C-reactive protein (CRP) and regulating the MAPK signalling pathway. In addition, in vivo experiments showed that JDSJY reduced skin inflammation and inhibited apoptosis, significantly ameliorated mitochondrial damage in keratinocytes, and reduced the levels of antioxidant-related indicators.

Conclusion: Comprehensive network pharmacology and in vivo experiments revealed that JDSJY's therapeutic efficacy in RD is mediated by ameliorating oxidative stress and maintaining mitochondrial homeostasis in keratinocytes.

Background: Chemotherapy remains a primary treatment for stopping cancer cell growth. Unfortunately, resistance to chemotherapy is a challenge that leads to cancer relapse. Overexpression of the antiapoptotic proteins is a major cause of this resistance. BH3 mimetic compounds were developed in this work to deal with this issue by blocking the Bcl-2 antiapoptotic proteins. Currently, only a few BH3 mimetics are approved drugs, and even fewer can effectively target all antiapoptotic Bcl-2 proteins.

Objective: The present study aimed to explore and screen the prodiginine family of molecules for new potential and effective BH-3 mimetics.

Methods: Molecular docking and molecular dynamics (MD) simulations were used to assess the potential of 30 prodiginine analogs as BH3 mimetics, including the obatoclax molecule, a prodiginine member used in clinical trials as a BH3 mimetic.

Results: Molecular docking results showed four prodiginines to have lower free binding energy values for five Bcl-2 proteins (Bcl-2, Mcl-1, Bcl-w, Bcl-xl, and Bfl1) compared to the reference drug, obatoclax. The five analogs presented safe pharmacological profiles according to Lipinski's rule of five. Furthermore, MD simulations demonstrated butylcycloheptyl prodiginine- Bcl-2 and prodigiosin-R2-Bcl-xl complexes to be more stable than the reference complexes obatoclax-Bcl-2 and obatoclax-Bcl-xl.

Conclusion: Based on these results, butylcycloheptyl prodigiosin and prodigiosin-R2 could be more effective BH3 mimetics and should be further studied.