17 research outputs found
Discovery of novel IDO1/TDO2 dual inhibitors: a consensus Virtual screening approach with molecular dynamics simulations, and binding free energy analysis
No full textThe pursuit of effective cancer immunotherapy drugs remains challenging, with overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) allowing cancer cells to evade immune attacks. While several IDO1 inhibitors have undergone clinical testing, only three dual IDO1/TDO2 inhibitors have reached human trials. Hence, this study focuses on identifying novel IDO1/TDO2 dual inhibitors through consensus structure-based virtual screening (SBVS). ZINC15 natural products library was refined based on molecular descriptors, and the selected compounds were docked to the holo form IDO1 and TDO2 using two different software programs and ranked according to their consensus docking scores. The top-scoring compounds underwent in silico evaluations for pharmacokinetics, toxicity, CYP3A4 affinity, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations. Five compounds (ZINC00000079405/10, ZINC00004028612/11, ZINC00013380497/12, ZINC00014613023/13, and ZINC00103579819/14) were identified as potential IDO1/TDO2 dual inhibitors due to their high consensus docking scores, key residue interactions with the enzymes, favorable pharmacokinetics, and avoidance of CYP3A4 binding. MD simulations of the top three hits with IDO1 indicated conformational changes and compactness, while MM-GBSA analysis revealed strong binding free energy for compounds 10 (ΔG: −20.13 kcal/mol) and 11 (ΔG: −16.22 kcal/mol). These virtual hits signify a promising initial step in identifying candidates as supplementary therapeutics to immune checkpoint inhibitors in cancer treatment. Their potential to deliver potent dual inhibition of IDO1/TDO2, along with safety and favorable pharmacokinetics, makes them compelling. Validation through in vitro and in vivo assays should be conducted to confirm their activity, selectivity, and preclinical potential as holo IDO1/TDO2 dual inhibitors. Communicated by Ramaswamy H. Sarma
Functional network analysis of p85 and PI3K as potential gene targets and mechanism of oleanolic acid in overcoming breast cancer resistance to tamoxifen
No full textBACKGROUND: Tamoxifen resistance in estrogen receptor positive (ER+) breast cancer therapy increases, which is the leading cause of cancer treatment failure, as it can impair patients’ prognoses, cause cancer recurrence, metastasis, and death. Combination therapy with compounds is needed to overcome tamoxifen resistance. Oleanolic acid (OA) was known to increase tamoxifen sensitivity in tamoxifen-resistant breast cancer; however, the molecular mechanism of OA and its involvement in overcoming tamoxifen resistance remain unknown and need further investigation. This study was conducted to identify the potential gene targets and molecular mechanisms of OA in overcoming tamoxifen resistance. RESULTS: A bioinformatic approach for functional network analysis was used in silico by utilizing secondary data in the Gene Expression Omnibus (GEO) database and analyzing them with GEO2R to obtain data on differentially expressed genes (DEGs). The DEG data were further examined with Database for Annotation, Visualization, and Integrated Discovery (DAVID), STRING, cBioPortal website, and Cytoscape with its plugin CytoHubba. Molecular docking was performed to predict the binding properties of OA on the protein encoded by the potential gene. CD44, FGFR2, PIK3R1, and MDM2 were designated as potential target genes (PTGs), and PIK3R1 was suspected as the potential gene for OA to overcome tamoxifen resistance. Molecular docking confirms that OA can inhibit p85 activation. PIK3R1 is suggested to be the potential gene for OA in overcoming tamoxifen resistance in breast cancer therapy. CONCLUSION: The predicted molecular mechanism of OA in overcoming tamoxifen resistance involves inhibiting p85 activation, leading to the inhibition of the downstream activity of the PI3K signaling pathway, causing breast cancer to respond to tamoxifen therapy once again. Results of this study need to be validated by further studies, including in vitro and in vivo. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s43141-022-00341-4
Discovery of novel IDO1/TDO2 dual inhibitors: a consensus Virtual screening approach with molecular dynamics simulations, and binding free energy analysis
No full textThe pursuit of effective cancer immunotherapy drugs remains challenging, with overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) allowing cancer cells to evade immune attacks. While several IDO1 inhibitors have undergone clinical testing, only three dual IDO1/TDO2 inhibitors have reached human trials. Hence, this study focuses on identifying novel IDO1/TDO2 dual inhibitors through consensus structure-based virtual screening (SBVS). ZINC15 natural products library was refined based on molecular descriptors, and the selected compounds were docked to the holo form IDO1 and TDO2 using two different software programs and ranked according to their consensus docking scores. The top-scoring compounds underwent in silico evaluations for pharmacokinetics, toxicity, CYP3A4 affinity, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations. Five compounds (ZINC00000079405/10, ZINC00004028612/11, ZINC00013380497/12, ZINC00014613023/13, and ZINC00103579819/14) were identified as potential IDO1/TDO2 dual inhibitors due to their high consensus docking scores, key residue interactions with the enzymes, favorable pharmacokinetics, and avoidance of CYP3A4 binding. MD simulations of the top three hits with IDO1 indicated conformational changes and compactness, while MM-GBSA analysis revealed strong binding free energy for compounds 10 (ΔG: −20.13 kcal/mol) and 11 (ΔG: −16.22 kcal/mol). These virtual hits signify a promising initial step in identifying candidates as supplementary therapeutics to immune checkpoint inhibitors in cancer treatment. Their potential to deliver potent dual inhibition of IDO1/TDO2, along with safety and favorable pharmacokinetics, makes them compelling. Validation through in vitro and in vivo assays should be conducted to confirm their activity, selectivity, and preclinical potential as holo IDO1/TDO2 dual inhibitors. Communicated by Ramaswamy H. Sarma</p
Caesalpinia sappan L. Ethanolic Extract Decrease Intracellular ROS Level and Senescence of 4T1 Breast Cancer Cells
Get PDFHighly and uncontrolled cell proliferation on cancer cells may boost ROS level intracellular accumulation up significantly. Sappan heartwood (Caesalpinia sappan L.) have been known to have cytotoxicity effect toward several cancer cells. This research was conducted to develop Caesalpinia sappan L. heartwood ethanolic extract (CSE) as chemopreventive agent which can be used as cancer therapy, looked from antioxidant and anti-senescence activity toward 4T1 breast cancer cell. CSE was obtained through maceration using ethanol 70% as solvent. Cytotoxicity activity of CSE was done by using MTT assay with IC50 as parameter. This IC50 was used as basic to the next assay, ROS assay by using DCFDA staining flowcytometry to look ROS level intracellular of CSE toward 4T1 cell and senescence assay by using senescence associated β-galactosidase (SA β-gal) assay with % cell senescence as their parameter. CSE toxic to 4T1 cell that proved from IC50 value of 25 µg/mL. Single treatment of CSE on concentration 12,5; 25; and 37.5 µg/mL able to suppress ROS level intracellular. If compared with untreated cell, single treatment of CSE on concentration 6 and 12 µg/mL showed % cell senescence not significantly different. Based on this result, CSE is cytotoxic, has antioxidant and antisenescence activity, so it has great potential to developed as chemoprevention agent on cancer therapy.Keywords : Caesalpinia sappan L., 4T1 breast cancer line, Reactive Oxygen Species (ROS), anti-senescenc
Desain Playground Indoor Modular di Rumah dengan Adaptasi Metode Montessori untuk Anak Usia 2 – 4 Tahun
No full textBerangkat dari permasalahan akan bermain adalah esensial untuk pertumbuhan saraf motorik, sensorik dan perkembangan kecerdasan intelektualnya. Untuk bermain anak-anak membutuhkan media seperti mainan. Salah satu mainan yang dapat mengembangkan saraf motorik dan sensorik adalah playground. Sedangkan anak dengan usia prasekolah (2 – 4 tahun) tidak mendapatkan akses untuk bermain di playground satu-satunya playground yang didapat jika orangtua membeli playground indoor.. Metode Montessori adalah metode yang paling efektif digunakan sebagai metode pembelajaran, sementara mainan dengan metode Montessori masih sulit ditemukan di Indonesia karena produksinya dari luar negeri. Playground perancangan adalah playground yang menerapkan metode Montessori untuk perkembangan kognitifnya. Keterbatasan lahan di Indonesia sekarang juga menjadi perhatian khusus untuk keluarga kecil yang memiliki anak usia prasekolah (2 – 4 tahun). Dengan ruang yang semakin menyempit dapat berpengaruh terhadap perkembangan anak. Penulis menemukan peluang pengembangan playground indoor di rumah untuk anak prasekolah usia 2 – 4 tahun dengan adaptasi metode Montessori. Pengumpulan data dilakukan dengan melakukan metode in-depth interview, shadowing, studi literatur dan komparasi produk eksisting yang menghasilkan affinity diagram, CJM berdasarkan kebutuhan user. Pengembangan desain dilakukan dari brainstorming, benchmarking, dan modelling yang diuji melalui usability testing. Tahapan diatas kemudian menghasilkan konsep produk berupa playground indoor modular di rumah dengan adaptasi metode Montessori untuk merangsang kecerdasan intelektual dan akomodasi wahana bermain anak usia prasekolah atau 2 – 4 tahun.
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Departing from the problem of playing is essential for the growth of motor, sensory nerves and the development of intellectual intelligence. To play children need media such as toys. One of the toys that can develop motor and sensory nerves is a playground. Whereas children with preschool age (2 – 4 years) do not get access to play on the playground. The only playground they get just because parents buy an indoor playground. The Montessori method is the most effective method used than other learning method, while toys with the Montessori method are still difficult to found in Indonesia because the production usually is import from abroad. The design of playground is a playground that applies the Montessori method for the cognitive development. Limited land in Indonesia is now also a special concern for small families with preschool children (2 – 4 years) which is can affect the development of children. Author found opportunities to develop indoor playgrounds at home for pre-schoolers aged 2-4 years with an adaptation of the Montessori method. Data collection was carried out using in-depth interviews, shadowing, literature studies and comparisons of existing products to produce affinity diagrams, CJM based on user needs. Design development is carried out from brainstorming, benchmarking, and modelling which is tested through usability testing. The steps above then produce a product concept in the form of a modular indoor playground at home with an adaptation of the Montessori method to stimulate intellectual intelligence and accommodation for pre-schoolers (2-4 year old)
MDM2 is a Potential Target Gene of Glycyrrhizic Acid for Circumventing Breast Cancer Resistance to Tamoxifen: Integrative Bioinformatics Analysis
No full textBACKGROUND: Tamoxifen is the drug of choice for treating breast cancer, particularly the estrogen receptor-positive luminal A subtype. However, the increased occurrence of Tamoxifen resistance highlights the need to develop an agent to enhance the effectiveness of this drug. OBJECTIVE: Although glycyrrhizic acid (GA) is known to exhibit cytotoxic effects on Michigan Cancer Foundation-7 cells, the specific gene targets and pathways it employs to overcome Tamoxifen resistance are incompletely understood. Therefore, the goal of the present research is to discover the potential targets and pathways of GA by using a bioinformatics approach. METHODS: Differentially expressed genes (DEGs) were identified in the Gene Expression Omnibus NCBI database using microarray data from GSE67916 and GSE85871. Further analyses were performed on these DEGs by using DAVID v6.8, STRING-DB v11.0, and Cytoscape v3.8.0. Analysis of gene alterations was performed using cBioPortal for target validation, and the relevant interaction process was examined via the molecular docking method. RESULTS: Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses identified the PI3K-AKT signaling as the potential target mechanism. Construction of the protein–protein interaction network and analysis of hub genes identified the top 25 hub genes. Genetic alterations were observed in six potential target genes, such as CDK2, MDM2, NF1, SMAD3, PTPN11, and CALM1. Molecular docking analysis demonstrated that the docking score of GA is lower than that of the native ligand of p53. More importantly, 3n the PI3K-AKT signaling pathway is a potential target for overcoming Tamoxifen resistance in breast cancer. C CONCLUSION: MDM2 may be a potential gene target of GA and the PI3K-AKT signaling may be a prospective mechanism for overcoming Tamoxifen resistance in breast cancer cells. Additional research is required to validate the findings of this study
Additional file 1 of Functional network analysis of p85 and PI3K as potential gene targets and mechanism of oleanolic acid in overcoming breast cancer resistance to tamoxifen
No full textAdditional file 1: Supplementary Figure 1. Distribution of the value obtained from the GEO database. The distribution of data for data series GSE67916 (A) and GSE86871 (B) is quite good
Computational Screening Using a Combination of Ligand-Based Machine Learning and Molecular Docking Methods for the Repurposing of Antivirals Targeting the SARS-CoV-2 Main Protease
No full textBackground: COVID-19 is an infectious disease caused by SARS-CoV-2, a close relative of SARS-CoV. Several studies have searched for COVID-19 therapies. The topics of these works ranged from vaccine discovery to natural products targeting the SARS-CoV-2 main protease (Mpro), a potential therapeutic target due to its essential role in replication and conserved sequences. However, published research on this target is limited, presenting an opportunity for drug discovery and development. Method: This study aims to repurpose 10692 drugs in DrugBank by using ligand-based virtual screening (LBVS) machine learning (ML) with Konstanz Information Miner (KNIME) to seek potential therapeutics based on Mpro inhibitors. The top candidate compounds, the native ligand (GC-376) of the Mpro inhibitor, and the positive control boceprevir were then subjected to absorption, distribution, metabolism, excretion, and toxicity (ADMET) characterization, drug-likeness prediction, and molecular docking (MD). Protein–protein interaction (PPI) network analysis was added to provide accurate information about the Mpro regulatory network. Results: This study identified 3,166 compound candidates inhibiting Mpro. The random forest (RF) molecular access system ML model provided the highest confidence score of 0.95 (bromo-7-nitroindazole) and identified the top 22 candidate compounds. Subjecting the 22 candidate compounds, the native ligand GC-376, and boceprevir to further ADMET property characterization and drug-likeness predictions revealed that one compound had two violations of Lipinski’s rule. Additional MD results showed that only five compounds had more negative binding energies than the native ligand (− 12.25 kcal/mol). Among these compounds, CCX-140 exhibited the lowest score of − 13.64 kcal/mol. Through literature analysis, six compound classes with potential activity for Mpro were discovered. They included benzopyrazole, azole, pyrazolopyrimidine, carboxylic acids and derivatives, benzene and substituted derivatives, and diazine. Four pathologies were also discovered on the basis of the Mpro PPI network. Conclusion: Results demonstrated the efficiency of LBVS combined with MD. This combined strategy provided positive evidence showing that the top screened drugs, including CCX-140, which had the lowest MD score, can be reasonably advanced to the in vitro phase. This combined method may accelerate the discovery of therapies for novel or orphan diseases from existing drugs. Graphical abstract: [Figure not available: see fulltext.
Additional file 2 of Functional network analysis of p85 and PI3K as potential gene targets and mechanism of oleanolic acid in overcoming breast cancer resistance to tamoxifen
No full textAdditional file 2: Supplementary Table 1. DEGs of tamoxifen-resistant MCF-7 cell line (GSE67916). Supplementary Table 2. DEGs of the MCF-7 cell line treated with OA (GSE85871). Supplementary Table 3. GO enrichment analysis of the OTGs : Biological Process. Supplementary Table 4. GO enrichment analysis of the OTGs : Cellular component. Supplementary Table 5. GO enrichment analysis of the OTGs : Molecular Function. Supplementary Table 6. KEGG pathway enrichment analysis of the OTGs
PENGARUH EKSTRAK KAYU SECANG (Caesalpinia sappan L.) TERHADAP ENZIM GLUTATION S-TRANSFERASE (GST) PADA SEL KANKER 4T1
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