Current computer-aided drug design最新文献

Background: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer lacking specific receptors, with dysregulated and overactivated Hedgehog (Hh) and mTOR/PI3K/AKT signaling pathways as potential therapeutic targets.

Objective: This study aimed to identify potential inhibitors among 53 alkaloids derived from 9 marine bryozoans using in silico approaches. It sought to analyze their impact on key signaling targets and their potential for future experimental validation.

Methods: In this research, selected targets were evaluated for protein-protein interactions, coexpression survival, and expression profiles. The protein expression was validated through the Human Protein Atlas (HPA) database and druggability through DGIdb. Online web servers were employed to assess drug-likeness, physiochemical properties, pharmacokinetics, and toxicological characteristics of the compounds. Molecular docking and dynamic simulations were carried out for ligand-protein interactions. Common Pharmacophore features, bioavailability, bioactivity, and biological activity spectrum (BAS) were also analyzed.

Results: Out of the 13 compounds studied, 10 displayed strong binding affinity with binding energies ranging from >-6.5 to <-8 Kcal/mol across all targets. Molecular dynamics simulations provided insights into Amathamide E's stability and conformational changes. Pharmacophore modeling revealed common features in 14 compounds potentially responsible for their biological activity.

Conclusion: Our findings indicate the potential of marine-derived compounds as TNBC inhibitors. Further in vitro and in vivo validation is necessary to establish their effectiveness and explore their role as novel anti-TNBC agents.

Background: The Computer-Aided Drug Discovery (CADD) approach was used to develop a few Epidermal Growth Factor Receptor (EGFR) kinase inhibitors. EGFR kinase expression is highly associated with genomic instability, higher proliferation, lower hormone receptor levels, and HER2 over-expression. It is more common in breast cancer. Thus, EGFR Kinase is one of the main targets in discovering new cancer medicine.

Objectives: To computationally validate some amides substituted β-amino enones as EGFR inhibitors and to carry out associated in vitro anticancer agents.

Methods: We used tools such as molecular docking, MD simulations, DFT calculations, and ADMET predictions in silico to establish a preliminary SAR. in vitro, we used BT474 (ER+HER2+) and MCF-7 (ER-HER2) cell lines along with normal breast cell epithelial cells (MFC-10a) for anticancer studies and EGFR kinase inhibition assay studies. As the Reactive Oxygen Species (ROS) plays the main role in cancer development, we also analyzed the antioxidant potentials of these compounds.

Results: Among the family of eleven amides substituted (Z)-β-amino enones (5a-k), compounds 5b, 5c, 5g, and 5h showed valuable in silico and in vitro bio-activity. Remarkably, the in-silico results almost coincided with in vitro study results.

Conclusion: We recommend compounds 5b, 5c, 5g, and 5h for pre-clinical and clinical evaluation to establish them as future cancer therapeutics.

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.

Background: MicroRNA-584-5p (miR-584-5p) plays an important role in certain types of cancer. However, its precise role in head and neck squamous cell carcinoma (HNSC) remains unknown.

Objective: Our aim was to investigate how miR-584-5p influences HNSC.

Methods: The Cancer Genome Atlas (TCGA) provided samples for the study. We use statistical methods to evaluate the diagnostic value, the prognostic value, and the correlation with the clinical features of miR-584-5p. We analyze the target genes and the regulatory network of miR- 584-5p. Quantitative reverse transcriptase PCR (qRT-PCR) confirmed the expression of miR- 584-5p in HNSC cell lines.

Results: MiR-584-5p expression of miR-584-5p varied significantly among different types of cancer. A notable correlation was observed between elevated miR-584-5p expression and gender (p < 0.001) and histological grade (p < 0.001). Furthermore, high levels of miR-584-5p were found to be associated with a decrease in overall survival (HR: 1.44; 95% CI: 1.10-1.88; p = 0.007), progression-free survival (HR: 1.35; 95% CI: 1.02-1.79; p = 0.035) and disease-specific survival (HR: 1.54; 95% CI: 1.09-2.18; p = 0.016) in the context of HNSC. miR-584-5p demonstrated independent prognostic significance in HNSC and potentially contributes to disease progression through multiple pathways, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In particular, HNSC cell lines exhibited a substantial upregulation of miR-584-5p compared to normal epithelial cells.

Conclusion: It is possible that miR-584-5p could serve as a promising patent for a therapeutic target and prognostic biomarker for people with HNSC.

Background: Estrogen alpha has been recognized as a perilous factor in breast cancer cell proliferation and has been proficiently treated in breast cancer chemotherapy with the development of selective estrogen receptor modulators (SERMs).

Objectives: The major aim of this study was to identify the potential inhibitors against the most influential target ERα receptor by in silico studies of 115 phytochemicals from 17 medicinal plants using in silico molecular docking studies.

Methods: The molecular docking investigation was carried out by a genetic algorithm using the Auto Dock Vina program, and the validation of docking was also performed using molecular dynamic (MD) simulation by the Desmond tool of Schrödinger molecular modeling. The ADME( T) studies were performed by SWISS ADME and ProTox-II.

Results: The top ten highest binding energy phytochemicals identified were amyrin acetate (- 10.7 kcal/mol), uscharine (-10.5 kcal/mol), voruscharin (-10.0 kcal/mol), cyclitols (-10.0 kcal/mol), taraxeryl acetate (-9.9 kcal/mol), amyrin (-9.9 kcal/mol), barringtogenol C (-9.9 kcal/mol), calactin (-9.9 kcal/mol), 3-beta taraxerol (-9.8 kcal/mol), and calotoxin (-9.8 kcal/mol). A molecular docking study revealed that these phytochemical constituents showed higher binding affinity compared to the reference standard tamoxifen (-6.6 kcal/mol) towards the target protein ERα. The results of MD studies showed that all four tested compounds possess comparatively stable ligand-protein complexes with ERα target as compared to the tamoxifen- ERα complex.

Conclusion: Among the ten compounds, phytochemical amyrin acetate (triterpenoids) formed a more stable complex as well as exhibited greater binding affinity than standard tamoxifen. ADMET studies for the top ten phytochemicals showed a good safety profile. Additionally, these compounds are being reported for the first time in this study as possible inhibitors of ERα for the treatment of breast cancer by adopting the concept of drug repurposing. Hence, these phytochemicals can be further studied and can be used as a parent core molecule to develop novel lead molecules for breast cancer therapy.

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: The incidence of CRC has increased worldwide over the past decade. The statistics report from WHO highlights the increased severity and fatality rate of CRC among the populations. Wnt/β-catenin is recognized as the resource for cell regeneration and cancer signaling pathways driven by frizzled receptor cofactors. Aberrant regulation of Wnt/β- catenin suppression is an important challenge in treating CRC management.

Aims and objective: The SFRP1 comprises a cysteine-rich region that is homologous to the putative Wnt-binding sites of Frizzled proteins, with the potential to impede and alter the cascade of Wnt signaling. Indirect regulation, like targeting Wnt antagonist SFRP1, is an alternative strategy to suppress the cancer signals by enhancing the apoptotic activity. Hence, this study aimed to approach the SFRP1 protein as a therapeutic target to inhibit Wnt signaling in colorectal cancer. Further, it aimed to identify the lead compounds against the SFRP1 protein, to inhibit the oncogenic expression of CRC, which might be possible and druggable using computational approaches, recognizing the importance of the SFRP1 protein role in CRC.

Methods: The homology-modeled SFRP1 structure was refined, and virtual screening was performed against the anti-cancer drugs and natural drug databases to find the best hit molecules. The molecular docking, MD, and MMGBSA analysis confirmed the firm binding of SFRP1 complexes to identify the potent CRC inhibitors.

Results: The amino acid residues Arg5, Arg11, Ala13, Lys 245, Lys274, Phe147, Pro99, and Ser277 are essential for ligand binding and show similar interactions for SFRP1 complexes. The ADME/T profile for top hits is acceptable in range and obtains the drug-likeness property. The 100ns run for MD simulation confirms the stability of protein complexes.

Conclusion: Overall, the findings of this study reveal that the lead compounds screened are capable of inhibiting SFRP1 against CRC. Targeting SFRP1 paves the way for new platforms in the field of cancer and the therapeutic sector for new approachable finds.