Current computer-aided drug design最新文献

Objective: This study utilized transcriptomic sequencing combined with cellular and animal models to explore the potential mechanisms of Xuebijing in treating sepsis-induced myocardial dysfunction, also known as sepsis-induced myocardial injury.

Methods: We investigated potential targets and regulatory mechanisms of XBJ injection using network pharmacology and RNA sequencing. The effects of XBJ on oxidative stress and apoptosis levels in human cardiac myocytes (AC16) and C57BL/6 mice exposed to lipopolysaccharide (LPS) were evaluated by Enzyme-Linked Immunosorbent Assay (ELISA), fluorescent probe, Fluorescent Quantitative Polymerase Chain Reaction (qPCR), Western Blot, Transmission Electron Microscopy, oxidative stress-related indicators detection kit, flow cytometry, and Immunohistochemistry (IHC).

Results: First, it was verified that XBJ can reduce the deformation of AC16 cardiomyocytes induced by LPS and the production and secretion of ROS (P <0.01). The transcriptome sequencing results showed that the TRIM16 gene was significantly increased after XBJ treatment, and the data of KEGG and GO analyses demonstrated that XBJ could inhibit the pathway expression of oxidative stress damage in AC16 cells, and PCR verified that XBJ could indeed increase the expression level of TRIM16 gene in AC16 cells (P <0.01). Basic animal and cell experiments showed that LPS could inhibit the expression of TRIM16 and NRF2 in cardiomyocytes (P <0.05) and promote the expression of Keap1 (P <0.01), while XBJ could significantly upregulate the expression levels of TRIM16 and NRF2 (P <0.01) and inhibit the expression of Keap1 (P <0.01), thereby affecting the expression levels of downstream proinflammatory cytokines and alleviating LPS-induced oxidative stress damage. In addition, XBJ also inhibited the expression of the pro-apoptotic proteins Bax and c-caspase3 (P <0.01), promoted the expression of the anti-apoptotic protein Bcl2 (P <0.01), and reduced LPS-induced apoptosis by upregulating TRIM16.

Conclusion: Our comprehensive data demonstrated that TRIM16 is a key gene in the therapeutic action of Xuebijing in sepsis-induced myocardial dysfunction, protecting myocardial cells from injury through antioxidative stress and anti-apoptotic mechanisms.

Objective: The Qing'e Pill (QEP) is widely used to alleviate low back pain and sciatica caused by Intervertebral Disc Degeneration (IDD). However, its active components, key targets, and molecular mechanisms are not fully understood. The aim of this study is to elucidate the molecular mechanisms through which the QEP improves IDD using database mining techniques.

Methods: Active components and candidate targets of the QEP were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and the Bioinformatics Analysis Tool for Molecular Mechanisms of Traditional Chinese Medicine. IDD-related targets were obtained from the GeneCards database, and liver- and kidney-specific genes were retrieved from the BioGPS database. The intersection of these candidate targets was analyzed to identify potential targets for the QEP in IDD. A protein-protein interaction network analysis was performed using STRING and Cytoscape 3.7.2 software. Core targets were further analyzed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking was used to assess the binding affinity of active components to candidate targets, and animal experiments were conducted for validation.

Results: We identified 65 potentially active components of the QEP that corresponded to 1,093 candidate targets, 2,108 IDD-related targets, and 1,113 liver- and kidney-specific genes. Key components included quercetin, berberine, isorhamnetin, and emodin. The primary candidate targets were Wnt5A, CTNNB1, IL-1β, MAPK14, MMP9, and MMP3. The GO and KEGG analyses revealed the involvement of these targets in Wnt signaling, TNF signaling, Wnt receptor activation, Frizzled binding, and Wnt-protein interactions. Molecular docking showed strong binding between these components and their targets. Animal experiments demonstrated that the QEP treatment significantly reduced the expression of Wnt5A, CTNNB1, IL-1β, MAPK14, MMP9, and MMP3 at high, medium, and low doses compared with the model group.

Conclusion: The QEP alleviated IDD by modulating the Wnt/MAPK/MMP signaling pathways and reducing the release and activation of key factors.

Background: Hyperlipidemia is characterized by an abnormally elevated serum cholesterol, triglycerides, or both. The relationship between an elevated level of LDL and cardiovascular diseases is well-established. Cholesteryl ester transfer protein (CETP) is an enzyme that moves cholesterol esters and triglycerides between LDL, VLDL, and HDL. CETP inhibition leads to a reduction in cardiovascular disease by raising HDL and minimizing LDL.

Objective: This study synthesized ten meta-chlorinated benzene sulfonamides 6a-6j and explored their structure-activity relationship.

Methods: The synthesized molecules were characterized using ¹H-NMR, ¹³C-NMR, IR, and HR-MS. Moreover, cheminformatics analyses included pharmacophore mapping, LibDock studies, and cheminformatics characterization using 2-dimensional (2D) molecular descriptors and principal component analysis.

Results: Based on in vitro functional CETP assays, compounds 6e, 6i, and 6j demonstrated the strongest inhibitory activities against CETP, reaching 100% inhibition. The inhibitory activity of compounds 6a-6d and 6f-6h ranged from 47.5% to 96.5% at 10 μM concentration. Pharmacophore mapping results suggested CETP inhibitory action, while the docking scores and calculated binding energies predicted favoring binding at the CETP active site. Best-scoring docking poses predicted critical hydrophobic features corresponding to key interactions with His232 and Cys13. Cheminformatics analysis using 2D molecular descriptors indicated that the synthesized compounds span various physicochemical properties and drug-likeness.

Conclusion: It was found that a chloro moiety at the ortho-position, or a nitro group at the meta and para-positions, improves the CETP inhibitory activity of synthesized analogs. Computational studies suggest the formation of stable ligand-protein complexes between compounds 6a- 6j and CETP.

Introduction: It has been reported that the extension of conjugation in chalcone scaffolds considerably enhanced the potency, selectivity, reversibility, and competitive mode of MAO-B inhibition. In this study, using the experimental results of IC50 values of fifteen halogenated conjugated dienone derivatives (MK1-MK15) against MAO-B, we developed a 3DQSAR model.

Methods: Further, we created a 3D pharmacophore model in active compounds in the series. The built model selected three variables (G2U, RDF115m, RDF155m) among the 653 AlvaDesc molecular descriptors, with a r² value of 0.87 and a Q² _cv for cross-validation equal to 0.82. The three variables were mostly associated with the direction of symmetry and the likelihood of discovering massive atoms at great distances. The evaluated molecules exhibited a good correlation between experimental and predicted data, indicating that the IC₅₀ value of the structure MK2 was related to the interatomic distances of 15.5 Å between bromine and chloro substituents. Furthermore, the molecules in the series with the highest activity were those with enhanced second component symmetry directional index from the 3D representation, which included the structures MK5 and MK6.

Results: Additionally, a pharmacophore hypothesis was developed and validated using the decoy Schrodinger dataset, with an ROC score of 0.87 and an HHRR 1 fitness score that ranged from 2.783 to 3.00. The MK series exhibited a significant blood-brain barrier (BBB) permeability, according to exploratory analyses and in silico projections, and almost all analogues were expected to have strong BBB permeability.

Conclusion: Further DFT research revealed that electrostatics were important in the interactions with MAO-B.

Objectives: The study aimed to explore the crucial genes involved in cancer-related biological processes, including EMT, autophagy, apoptosis, anoikis, and metastasis. It also sought to identify common genes among the pathways linked to these biological processes, determine the level of Bcl-2 expression in various types of cancers, and find a potent inhibitor of Bcl-2 among natural compounds.

Methods: Common genes involved in the pathways related to EMT, autophagy, apoptosis, anoikis, and metastasis were explored, and the level of the most frequently overexpressed gene that was Bcl-2, in various types of cancers was analyzed by gene expression analysis. A set of 102 natural compounds was sorted according to their docking scores using molecular docking and filtering. The top-ranked molecule was chosen for additional molecular dynamics (MD) simulation for 100 ns. Differential gene expression analysis was performed for Dioscin using GEO2R.

Results: The study identified four common genes, Bcl-2, Bax, BIRC3, and CHUK, among the pathways linked to EMT, autophagy, apoptosis, anoikis, and metastasis. Bcl-2 was highly overexpressed in many cancers, including Acute Myeloid Leukemia, Diffuse large B cell lymphoma, and Thymoma. The Dioscin structure in the Bcl-2 binding site received the highest docking score and the most relevant interactions. Dioscin's determined binding free energy by MM/GBSA was -52.21 kcal/mol, while the same calculated by MM/PBSA was -9.18 kcal/mol. A p-value of less than 0.05 was used to determine the statistical significance of the analysis performed using GEO2R. It was observed that Dioscin downregulates Bcl-2, BIRC3, and CHUK and upregulates the pro-apoptotic protein Bax.

Conclusion: The study concluded that Dioscin has the potential to act as a protein inhibitor, with a noteworthy value of binding free energy and relevant interactions with the Bcl-2 binding site. Dioscin might be a good alternative for targeting multiple cancer pathways through a single target.

Background: Sanguinarine (SAN) has been reported to have antioxidant, antiinflammatory, and antimicrobial activities with potential for the treatment of osteoporosis (OP).

Objective: This work purposed to unravel the molecular mechanisms of SAN in the treatment of OP.

Methods: OP-related genes and SAN-related targets were predicted from public databases. Differential expression analysis and VennDiagram were adopted to detect SAN-related targets against OP. Protein-protein interaction (PPI) network was served for core target identification. Molecular docking and DeepPurpose algorithm were further adopted to investigate the binding ability between core targets and SAN. Gene pathway scoring of these targets was calculated utilizing gene set variation analysis (GSVA). Finally, we explored the effect of SAN on the expressions of core targets in preosteoblastic MC3T3-E1 cells.

Results: A total of 21 candidate targets of SAN against OP were acquired. Furthermore, six core targets were identified, among which CASP3, CTNNB1, and ERBB2 were remarkably differentially expressed in OP and healthy individuals. The binding energies of SAN with CASP3, CTNNB1, and ERBB2 were -6, -6.731, and -7.162 kcal/mol, respectively. Moreover, the GSVA scores of the Wnt/calcium signaling pathway were significantly lower in OP cases than in healthy individuals. In addition, the expression of CASP3 was positively associated with Wnt/calcium signaling pathway. CASP3 and ERBB2 were significantly lower expressed in SAN group than in DMSO group, whereas the expression of CTNNB1 was in contrast.

Conclusion: CASP3, CTNNB1, and ERBB2 emerge as potential targets of SAN in OP prevention and treatment.

Objectives: Cancer poses a great threat to human health, and effective drugs to treat it are always needed. Several compounds containing a 2-aminopyrazine framework have been identified as antitumor agents with SHP2 inhibition activities. This current work aimed to search for more potent novel compounds possessing a 2-aminopyrazine moiety with antitumor activities.

Methods: A series of 12 novel 2-aminopyrazine derivatives was synthesized, and their structures were confirmed by spectroscopic techniques. The inhibitory activities of all the synthesized compounds against MDA-MB-231 and H1975 cancer cell lines were evaluated by an MTT assay. The most potent compound 3e was analyzed by flow cytometry. Subsequently, computational studies were performed to investigate the possible antitumor mechanisms of compound 3e.

Results: The results indicated that compound 3e exhibited potent antitumor activities with IC50 values of 11.84 ± 0.83 μM against H1975 cells and 5.66 ± 2.39 μM against MDA-MB-231 cells, which were more potent than the SHP2 inhibitor GS493 (IC₅₀ = 19.08 ± 1.01 μM against H1975 cells and IC₅₀ = 25.02 ± 1.47 μM against MDA-MB-231 cells). Further analysis by flow cytometry demonstrated that compound 3e induced cell apoptosis in H1975 cells. The results of the molecular docking and MD simulations, including RMSD, RMSF, PCA, DCCM and binding energy and decomposition analyses, revealed that compound 3e probably selectively inhibited SHP2.

Conclusion: A new compound having a 2-aminopyrazine substructure with potent inhibitory activities against the H1975 and MDA-MB-231 cancer cells was obtained, meriting further investigation as an antitumor drug.

Background: Acinetobacter baumannii is one of the main causes of nosocomial infections. No vaccine has yet been licensed for use in humans, and efforts are still ongoing.

Objective: In the present study, we have predicted the B-cell epitopes of A. baumannii's outer membrane protein K (OMPK) by using epitope prediction algorithms as possible vaccine candidates for future studies.

Methods: The linear B-cell epitopes were predicted by seven different prediction tools. The 3D structure of OMPK was modeled and used for discontinuous epitope prediction by ElliPro and DiscoTope 2.0 tools. The final linear epitopes and the discontinuous epitope segments were checked for potential allergenicity, toxicity, human similarity, and experimental records. The structure and physicochemical features of the final epitopic peptide were assessed by numerous bioinformatics tools.

Results: Many B-cell epitopes were detected that could be assessed for possible antigenicity and immunogenicity. Also, an epitopic 22-mer region (peptide) of OMPK was found that contained both linear and discontinuous B-cell epitopes. This epitopic peptide has been found to possess appropriate physicochemical and structural properties to be an A. baumannii vaccine candidate.

Conclusion: Altogether, here, the high immunogenic B-cell epitopes of OMPK have been identified, and a high immunogenic 22-mer peptide as an A. baumannii vaccine candidate has been introduced. The in vitro/in vivo studies of this peptide are recommended to decide its real efficacy and efficiency.

Aims and objectives: This study aimed to evaluate the pharmacological mechanism of Hederagenin (HD) combined with oxaliplatin (L-OHP) in treating gastric cancer (GC) through network pharmacology combined with experimental verification.

Material and methods: Network pharmacology methods were used to screen potential targets for HD, L-OHP, and GC-related targets from public databases, and the intersection of the three gene sets was taken. Cross genes were analyzed through protein-protein interaction (PPI) networks to predict core targets, and related pathways were predicted through GO and KEGG enrichment analysis. The experimental results were verified by the in vitro experiments. HD was applied on AGS/L-OHP cells, and then cellular chemosensitivity and the expressions of P-gp, Survivin, Bcl-2, p-Akt, and p-PI3K genes were detected. Wound assay and Transwell Chamber assay were employed to detect the effect of HD on AGS/L-OHP cells. Nude mice xenograft models transfected using AGS/L-OHP cells were also treated with HD in order to verify the results. The size and weight of the tumor, as well as the expressions of P-gp, Survivin, Bcl-2, p- Akt and p-PI3K genes, were also measured.

Results: KEGG analysis showed that the anti-gastric cancer effect of HD was mediated mainly by PI3K-Akt signaling pathways. The PI3K-Akt signaling pathway containing more enriched genes may play a greater role in anti-gastric cancer. It was observed that for AGS/L-OHP cells jointly treated with HD and L-OHP, their activity, migration and invasion were significantly lower than those treated only using HD or L-OHP group. Moreover, expressions of p-Akt, p- PI3K, Bcl-2, P-gp, and Survivin for the HD+L-OHP group decreased significantly. Results of the in vivo experiments showed that the sizes and weights of tumors in the HD+L-OHP group were the lowest compared to the HD group and L-OHP group.

Conclusion: Our findings suggest that HD may reduce the resistance of AGS/L-OHP cells to LOHP by regulating the PI3K/Akt signaling pathway.

Objectives: 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.