Target Characterization of Kaempferol against Myocardial Infarction Using Novel In Silico Docking and DARTS Prediction Strategy.
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ABSTRACT:
SUBMITTER: Wu X
PROVIDER: S-EPMC8657499 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The in silico single gene deletion step was adapted to simulate the knock-out of all targets of a drug on an objective function such as growth or energy balance. Based on publicly available and in-house large scale transcriptomic data, metabolic models for melanoma were reconstructed, enabling the prediction of 28 candidate drugs and estimating their respective efficacy.
| EGAS00001006463 | EGA
Project description:Identifying the molecular targets for the beneficial or detrimental effects of small-molecule drugs is an important and currently unmet challenge. We have developed a method, drug affinity responsive target stability (DARTS), which takes advantage of a reduction in the protease susceptibility of the target protein upon drug binding. DARTS is universally applicable because it requires no modification of the drug and is independent of the mechanism of drug action. We demonstrate use of DARTS to identify known small-molecule-protein interactions and to reveal the eukaryotic translation initiation machinery as a molecular target for the longevity-enhancing plant natural product resveratrol. We envisage that DARTS will also be useful in global mapping of protein-metabolite interaction networks and in label-free screening of unlimited varieties of compounds for development as molecular imaging agents.
| S-EPMC2789755 | biostudies-literature
Project description:Background During the second wave of the COVID-19 pandemic, an unusual increase in cases of mucormycosis was observed in India, owing to immunological dysregulation caused by the SARS-CoV-2 and the use of broad-spectrum antibiotics, particularly in patients with poorly controlled diabetes with ketoacidosis to have contributed to the rise, and it has been declared an epidemic in several states of India. Because of the black colouring of dead and dying tissue caused by the fungus, it was dubbed "black fungus" by several Indian media outlets. In this study, attempts were taken to unmask novel therapeutic options to treat mucormycosis disease. Rhizopus species is the primary fungi responsible for 70% of mucormycosis cases. Results We chose three important proteins from the Rhizopus delemar such as CotH3, Lanosterol 14 alpha-demethylase and Mucoricin which plays a crucial role in the virulence of Mucorales. Initially, we explored the physiochemical, structural and functional insights of proteins and later using AutoDock Vina, we applied computational protein–ligand binding modelling to perform a virtual screening around 300 selected compounds against these three proteins, including FDA-approved drugs, FDA-unapproved drugs, investigational-only drugs and natural bioactive compounds. ADME parameters, toxicity risk and biological activity of those compounds were approximated via in silico methods. Our computational studies identified six ligands as potential inhibitors against Rhizopus delemar, including 12,28-Oxamanzamine A, vialinin B and deoxytopsentin for CotH3; pramiconazole and saperconazole for Lanosterol 14 alpha-demethylase; and Hesperidin for Mucoricin. Interestingly, 12,28-Oxamanzamine A showed a maximum binding affinity with all three proteins (CotH3: − 10.2 kcal/mol Lanosterol 14 alpha-demethylase: − 10.9 kcal/mol Mucoricin: − 8.6 kcal/mol). Conclusions In summary, our investigation identified 12,28-Oxamanzamine A, vialinin B, deoxytopsentin, pramiconazole, saperconazole and hesperidin as potent bioactive compounds for treating mucormycosis that may be considered for further optimisation techniques and in vitro and in vivo studies. Supplementary Information The online version contains supplementary material available at 10.1186/s42269-022-00704-4.
| S-EPMC8802264 | biostudies-literature
Project description:Although numerous therapies are widely applied clinically and stem cells and/or biomaterial based in situ implantations have achieved some effects, few of these have observed robust myocardial regeneration. The beneficial effects on cardiac function and structure are largely acting through paracrine signaling, which preserve the border-zone around the infarction, reduce apoptosis, blunt adverse remodeling, and promote angiogenesis. Ionic extracts from biomaterials have been proven to stimulate paracrine effects and promote cell-cell communications. Here, the paracrine stimulatory function of bioactive ions derived from biomaterials is integrated into the clinical concept of administration and proposed "ion therapy" as a novel strategy for myocardial infarction. In vitro, silicon- enriched ion extracts significantly increase cardiomyocyte viability and promote cell-cell communications, thus stimulating vascular formation via a paracrine effect under glucose/oxygen deprived conditions. In vivo, by intravenous injection, the bioactive silicon ions act as "diplomats" and promote crosstalk in myocardial cells, stimulate angiogenesis, and improve cardiac function post-myocardial infarction.
| S-EPMC6325593 | biostudies-literature
Project description:Myocardial infarction is a prevalent and life-threatening cardiovascular disease. The main goal of existing interventional therapies is to restore coronary reperfusion while few are designed to ameliorate the pathology of heart diseases via targeting the post-translational modifications of those critical proteins. Small ubiquitin-like modifier (SUMO) proteins are recently discovered to form a new type of protein post-translational modifications (PTM), known as SUMOylation. SUMOylation and deSUMOylation are dynamically balanced in the maintenance of various biological processes including cell division, DNA repair, epigenetic transcriptional regulation, and cellular metabolism. Importantly, SUMOylation plays a critical role in the regulation of cardiac functions and the pathology of cardiovascular diseases, especially in heart failure and myocardial infarction. This review summarizes the current understanding on the effects of SUMOylation and SUMOylated proteins in the pathophysiology of myocardial infarction and identifies the potential treatments against myocardial injury via targeting SUMO. Ultimately, this review recommends SUMOylation as a key therapeutic target for treating cardiovascular diseases.
| S-EPMC8355363 | biostudies-literature
Project description:Melianone, the protolimonoid (24, 25-epoxyflindissone), was isolated from the medicinal tree species, Swietenia mahagoni (L.) JACQ (Meliaceae). The compound isolated from petroleum ether leaf extracts (5.39%) was quantified using high-performance thin-layer chromatography (HPTLC) method. In antimicrobial assays melianone inhibited Salmonella ser. Typhi with an MIC of 0.053 µM. Induced Fit Docking (IFD) of the ligand, melianone, with proteins involved in anaerobic virulence of the pathogen, revealed that it binds with FocA (a transport protein of formate ions) at its "periplasmic opening" with a glide energy of - 51.8576 kcal mol-1. Melianone altered the overall conformation of the protein (protomer A) by 0.347 Å RMSD. It induced a notable protein topology (Ω loop region) shift in the channel from an intermediate-open to a closed-state conformation and was supported by molecular dynamic simulations performed. FocA, a protein that contributes to its survival under anaerobic conditions, was further evaluated experimentally, after exposure of Salmonella ser. Typhi to melianone, resulting in the altered homeostasis of formate.
| S-EPMC7527380 | biostudies-literature
Project description:The need for new antimalarials is persistent due to the emergence of drug resistant parasites. Here we aim to identify new drug targets in Plasmodium falciparum by phylogenomics among the Plasmodium spp. and comparative genomics to Homo sapiens. The proposed target discovery pipeline is largely independent of experimental data and based on the assumption that P. falciparum proteins are likely to be essential if (i) there are no similar proteins in the same proteome and (ii) they are highly conserved across the malaria parasites of mammals. This hypothesis was tested using sequenced Saccharomycetaceae species as a touchstone. Consecutive filters narrowed down the potential target space of P. falciparum to proteins that are likely to be essential, matchless in the human proteome, expressed in the blood stages of the parasite, and amenable to small molecule inhibition. The final set of 40 candidate drug targets was significantly enriched in essential proteins and comprised proven targets (e.g. dihydropteroate synthetase or enzymes of the non-mevalonate pathway), targets currently under investigation (e.g. calcium-dependent protein kinases), and new candidates of potential interest such as phosphomannose isomerase, phosphoenolpyruvate carboxylase, signaling components, and transporters. The targets were prioritized based on druggability indices and on the availability of in vitro assays. Potential inhibitors were inferred from similarity to known targets of other disease systems. The identified candidates from P. falciparum provide insight into biochemical peculiarities and vulnerable points of the malaria parasite and might serve as starting points for rational drug discovery.
| S-EPMC3862442 | biostudies-literature
Project description:Cardioprotection refers to a strategy aimed at enhancing survival pathways in the injured yet salvageable myocardium following ischemia-reperfusion. Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor that can be targeted following reperfusion, to induce a cardioprotective signaling through the activation of the reperfusion injury salvage kinase (RISK) pathway. The data from preclinical studies with non-selective and selective LRP1 agonists are promising, showing a large therapeutic window for intervention to reduce infarct size after ischemia-reperfusion. A pilot clinical trial with plasma derived ?1-antitrypsin (AAT), a naturally occurring LRP1 agonist, supports the translational value of LRP1 as a novel therapeutic target for cardioprotection. A phase I study with a selective LRP1 agonist has been completed showing no toxicity. These findings may open the way to early phase clinical studies with pharmacologic LRP1 activation in patients with acute myocardial infarction (AMI).
| S-EPMC6387161 | biostudies-literature
Project description:MicroRNAs (miRNAs) are a class of highly conserved endogenous noncoding single-stranded small RNAs with a length of 18-22 nucleotides. They are involved in regulation at the posttranscriptional and translational levels through the degradation and translation inhibition of messenger RNA (mRNA). It is estimated that at least 60% of all mammalian genes may be regulated by miRNAs. MiRNAs can help uncover the mechanisms of diseases and provide new entry points into therapy. Accumulated evidence has revealed that miRNAs are involved in the pathological process of cardiovascular disease through specific signaling pathways. To investigate the potential miRNAs for myocardial fibrosis post myocardial infarction, rat models of acute myocardial infarction (AMI) were established by ligating the anterior descending branch of the left coronary artery, while sham-operated rats were only threaded without ligation as a control group. There were three rats in each group. Thirteen differentially expressed miRNAs between the two groups were screened and their expression levels in the model group were all higher than those in the control group. The expression of miR-199a-5p was significantly increased in the model group in qRT-PCR, which was consistent with the results of the gene chip. KEGG enrichment analysis showed that the target genes of miR-199a-5p were enriched in the insulin signaling pathway. Furthermore, dual-luciferase reporter assay indicated that miR-199a-5p could negatively regulate the expression of GSK-3β. After transfection, the expression of miR-199a-5p was increased in the miR-199a-5p mimics group. The protein expression of GSK-3β was decreased in CFs transfected with miR-199a-5p mimics. In summary, our study identified miR-199a-5p could promote the progression of myocardial fibrosis after myocardial infarction by targeting GSK-3β, which provides novel targets for diagnosis and treatment of MF. In summary, our research suggests that miR-199a-5p promotes the progression of myocardial fibrosis after myocardial infarction through the activation of the insulin-PI3K/Akt-GSK-3β signaling pathway.
2022-07-14 | GSE208159 | GEO
Project description:The purpose of this study was to demonstrate the feasibility of a combined cooling strategy started out of hospital as an adjunctive to percutaneous coronary intervention (PCI) in the treatment of ST-elevation acute coronary syndrome (STE-ACS).Non-randomised, single-centre feasibility trial.Department of emergency medicine of a tertiary-care facility, Medical University of Vienna, Vienna, Austria. In cooperation with the Municipal ambulance service of the city of Vienna.Consecutive patients with STE-ACS presenting to the emergency medical service within 6 h after symptom onset.Cooling was initiated with surface cooling pads in the out-of-hospital setting, followed by the administration of 1000-2000 mL of cold saline at hospital arrival and completed by endovascular cooling in the catheterisation laboratory.Feasibility of lowering core temperature below 35.0°C prior to immediately performed revascularisation. Safety and tolerability of the cooling procedure.In enrolled 19 patients (one woman, median age 51 years (IQR 45-59)), symptom onset to first medical contact (FMC) was 45 min (IQR 31-85). A core temperature below 35.0°C at reperfusion of the culprit lesion was achieved in 11 patients (78%) within 100 min (IQR 90-111) after FMC without any cooling-related serious adverse event. Temperature could be lowered from baseline 36.4°C (IQR 36.2-36.5°C) to 34.4°C (IQR 34.1-35.0°C) at the time of reperfusion.With limitations an immediate out-of-hospital therapeutic hypothermia strategy was feasible and safe in patients with STE-ACS undergoing primary PCI.http://www.clinicaltrials.gov/ct2/show/NCT01864343; clinical trials unique identifier: NCT01864343.
| S-EPMC3812852 | biostudies-literature