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The rise of pyrazinamide (PZA)-resistant strains of Mycobacterium tuberculosis (MTB) poses a major challenge to conventional tuberculosis (TB) treatments. PZA, a cornerstone of TB therapy, must be activated by the mycobacterial enzyme pyrazinamidase (PZase) to convert its active form, pyrazinoic acid, which targets the ribosomal protein S1. Resistance, often associated with mutations in the RpsA protein, complicates treatment and highlights a critical gap in the understanding of structural dynamics and mechanisms of resistance, particularly in the context of the G97D mutation. This study utilizes a novel integration of computational techniques, including multiscale biomolecular and molecular dynamics simulations, physicochemical and medicinal chemistry predictions, quantum computations and virtual screening from the ZINC and Chembridge databases, to elucidate the resistance mechanism and identify lead compounds that have the potential to improve treatment outcomes for PZA-resistant MTB, namely ZINC15913786, ZINC20735155, Chem10269711, Chem10279789 and Chem10295790. These computational methods offer a cost-effective, rapid alternative to traditional drug trials by bypassing the need for organic subjects while providing highly accurate insight into the binding sites and efficacy of new drug candidates. The need for rapid and appropriate drug development emphasizes the need for robust computational analysis to justify further validation through in vitro and in vivo experiments.
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Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Humanos , Pirazinamida/química , Pirazinamida/metabolismo , Pirazinamida/farmacologia , Mycobacterium tuberculosis/genética , Antituberculosos/química , Antituberculosos/metabolismo , Antituberculosos/farmacologia , Tuberculose/microbiologia , Mutação , Testes de Sensibilidade MicrobianaRESUMO
Gastric cancer is considered a class 1 carcinogen that is closely linked to infection with Helicobacter pylori (H. pylori), which affects over 1 million people each year. However, the major challenge to fight against H. pylori and its associated gastric cancer due to drug resistance. This research gap had led our research team to investigate a potential drug candidate targeting the Helicobacter pylori-carcinogenic TNF-alpha-inducing protein. In this study, a total of 45 daidzein derivatives were investigated and the best 10 molecules were comprehensively investigated using in silico approaches for drug development, namely pass prediction, quantum calculations, molecular docking, molecular dynamics simulations, Lipinski rule evaluation, and prediction of pharmacokinetics. The molecular docking study was performed to evaluate the binding affinity between the target protein and the ligands. In addition, the stability of ligand-protein complexes was investigated by molecular dynamics simulations. Various parameters were analysed, including root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), hydrogen bond analysis, principal component analysis (PCA) and dynamic cross-correlation matrix (DCCM). The results has confirmed that the ligand-protein complex CID: 129661094 (07) and 129664277 (08) formed stable interactions with the target protein. It was also found that CID: 129661094 (07) has greater hydrogen bond occupancy and stability, while the ligand-protein complex CID 129664277 (08) has greater conformational flexibility. Principal component analysis revealed that the ligand-protein complex CID: 129661094 (07) is more compact and stable. Hydrogen bond analysis revealed favourable interactions with the reported amino acid residues. Overall, this study suggests that daidzein derivatives in particular show promise as potential inhibitors of H. pylori.
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Helicobacter pylori , Isoflavonas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/metabolismo , Isoflavonas/farmacologia , Isoflavonas/química , Isoflavonas/metabolismo , Humanos , Ligação de Hidrogênio , Ligantes , Ligação Proteica , Análise de Componente Principal , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/tratamento farmacológico , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/antagonistas & inibidores , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Both diabetes and cancer pose significant threats to public health. To overcome these challenges, nanobiotechnology offers innovative solutions for the treatment of these diseases. However, the synthesis of nanoparticles can be complex, costly and environmentally toxic. Therefore, in this study, we successfully synthesized Camellia sinensis silver nanoparticles (CS-AgNPs) biologically from methanolic leaf extract of C. sinensis and as confirmed by the visual appearance which exhibited strong absorption at 456â nm in UV-visible spectroscopy. The fourier transform infrared spectroscopy (FTIR) analysis revealed that phytochemicals of C. sinensis were coated with AgNPs. Scanning electron microscopy (SEM) analysis showed the spherical shape of CS-AgNPs, with a size of 15.954â nm, while X-ray diffraction spectrometry (XRD) analysis detected a size of 20.32â nm. Thermogravimetric analysis (TGA) indicated the thermal stability of CS-AgNPs. The synthesized CS-AgNPs significantly inhibited the ehrlich ascites carcinoma (EAC) cell growth with 53.42±1.101 %. The EAC cell line induced mice exhibited increased level of the serum aspartate aminotransferase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP), however this elevated serum parameter significantly reduced and controlled by the treatment with CS-AgNPs. Moreover, in a streptozotocin-induced diabetic mice model, CS-AgNPs greatly reduced blood glucose, total cholesterol, triglyceride, low-density lipoprotein (LDL) and creatinine levels. These findings highlight that the synthesized CS-AgNPs have significant anticancer and antidiabetic activities that could be used as promising particles for the treatment of these major diseases. However, pre-clinical and clinical trial should be addressed before use this particles as therapeutics agents.
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Camellia sinensis , Diabetes Mellitus Experimental , Nanopartículas Metálicas , Neoplasias , Camundongos , Animais , Nanopartículas Metálicas/química , Prata/química , Camellia sinensis/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Extratos Vegetais/química , Espectroscopia de Infravermelho com Transformada de Fourier , Antibacterianos , Difração de Raios XRESUMO
The widespread emergence of antimalarial drug resistance has created a major threat to public health. Malaria is a life-threatening infectious disease caused by Plasmodium spp., which includes Apicoplast DNA polymerase and Plasmodium falciparum cysteine protease falcipain-2. These components play a critical role in their life cycle and metabolic pathway, and are involved in the breakdown of erythrocyte hemoglobin in the host, making them promising targets for anti-malarial drug design. Our current study has been designed to explore the potential inhibitors from haplopine derivatives against these two targets using an in silico approach. A total of nine haplopine derivatives were used to perform molecular docking, and the results revealed that Ligands 03 and 05 showed strong binding affinity compared to the control compound atovaquone. Furthermore, these ligand-protein complexes underwent molecular dynamics simulations, and the results demonstrated that the complexes maintained strong stability in terms of RMSD (root mean square deviation), RMSF (root mean square fluctuation), and Rg (radius of gyration) over a 100 ns simulation period. Additionally, PCA (principal component analysis) analysis and the dynamic cross-correlation matrix showed positive outcomes for the protein-ligand complexes. Moreover, the compounds exhibited no violations of the Lipinski rule, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions yielded positive results without indicating any toxicity. Finally, density functional theory (DFT) and molecular electrostatic potential calculations were conducted, revealing that the mentioned derivatives exhibited better stability and outstanding performance. Overall, this computational approach suggests that these haplopine derivatives could serve as a potential source for developing new, effective antimalarial drugs to combat malaria. However, further in vitro or in vivo studies might be conducted to determine their actual effectiveness.
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A trace element, known as a minor element, is a chemical element whose concentration is very low. They are divided into essential and non-essential classes. Numerous physiological and metabolic processes in both plants and animals require essential trace elements. These essential trace elements are so directly related to the metabolic and physiologic processes of the organism that either their excess or deficiency can result in severe bodily malfunction or, in the worst situations, death. Elements can be found in nature in various forms and are essential for the body to carry out its varied functions. Trace elements are crucial for biological, chemical, and molecular cell activity. Nutritional deficits can lead to weakened immunity, increased susceptibility to oral and systemic infections, delayed physical and mental development, and lower productivity. Trace element enzymes are involved in many biological and chemical processes. These compounds act as co-factors for a number of enzymes and serve as centers for stabilizing the structures of proteins and enzymes, allowing them to mediate crucial biological processes. Some trace elements control vital biological processes by attaching to molecules on the cell membrane's receptor site or altering the structure of the membrane to prevent specific molecules from entering the cell. Some trace elements are engaged in redox reactions. Trace elements have two purposes. They are required for the regular stability of cellular structures, but when lacking, they might activate alternate routes and induce disorders. Therefore, thoroughly understanding these trace elements is essential for maintaining optimal health and preventing disease.
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Oligoelementos , Animais , HumanosRESUMO
The α-D-glucopyranoside and its derivatives were as the cardinal investigation for developing an effective medication to treat the highest deadly white spot syndrome virus (WSSV) diseases in Shrimp. In our forthcoming work, both computational tools, such as molecular docking, quantum calculations, pharmaceutical kinetics, ADMET, and their molecular dynamics, as well as the experimental trial against WSSV, were executed to develop novel inhibitors. In the beginning, molecular docking was carried out to determine inhibitors of the four targeted proteins of WSSV (PDB ID: 2ED6, 2GJ2, 2GJI, and 2EDM), and to determine the binding energies and interactions of ligands and proteins after docking. The range of binding affinity was found to be between -5.40 and -7.00 kcal/mol for the protein 2DEM, from -5.10 to 6.90 kcal/mol for the protein 2GJ2, from -4.70 to -6.2 kcal/mol against 2GJI, and from -5.5 kcal/mol to -6.6 kcal/mol for the evolved protein 2ED6 whereas the L01 and L03 display the highest binding energy in the protein 2EDM. After that, the top-ranked compounds (L01, L02, L03, L04, and L05), based on their high binding energies, were tested for molecular dynamics (MD) simulations of 100 ns to verify the docking validation and stability of the docked complex by calculating the root mean square deviation (RMSD) and root mean square fluctuation (RMSF). The molecules with the highest binding energy were then picked and compared to the standard drugs that were been applied to fish experimentally to evaluate the treatment at various doses. Consequently, approximately 40-45% cure rate was obtained by applying the dose of oxytetracycline (OTC) 50% with vitamin C with the 10.0 g/kg feed for 10 days. These drugs (L09 to L12) have also been executed for molecular docking to compare with α-D-glucopyranoside and its derivatives (L01 to L08). Next, the evaluation of pharmacokinetic parameters, such as drug-likeness and Lipinski's principles; absorption; distribution; metabolism; excretion; and toxicity (ADMET) factors, were employed gradually to further evaluate their suitability as inhibitors. It was discovered that all ligands (L01 to L12) were devoid of hepatotoxicity, and the AMES toxicity excluded L05. Additionally, all of the compounds convey a significant aqueous solubility and cannot permeate the blood-brain barrier. Moreover, quantum calculations based on density functional theory (DFT) provide the most solid evidence and testimony regarding their chemical stability, chemical reactivity, biological relevance, reactive nature and specific part of reactivity. The computational and virtual screenings for in silico study reveals that these chosen compounds (L01 to L08) have conducted the inhibitory effect to convey as a possible medication against the WSSV than existing drugs (L09, L10, L11 and L12) in the market. Next the drugs (L09, L10, L11 and L12) have been used in trials.
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Simulação de Dinâmica Molecular , Vírus da Síndrome da Mancha Branca 1 , Animais , Ligantes , Simulação de Acoplamento Molecular , SulfadiazinaAssuntos
Infecções por Henipavirus , Henipavirus , Humanos , Henipavirus/genética , Virulência , GenômicaRESUMO
Background and Aims: Co-infections occur when two or more different types of pathogens infect the same host at the same time. Initially, it may develop via a primary infection and then later segue into a superinfection. Although some research suggests that coinfections do not affect the effect of disease outcomes, alternate evidence says otherwise. While the disease outcomes are frequently influenced by the interactions between many viruses, how these viruses interact during coinfections is poorly understood. This article aims to shed light on the interaction between viruses at a cellular and subcellular level, and the clinical implications for the same. Methods: The articles were sought by conducting a thorough literature search on Google Scholar, ScienceDirect, PubMed, PubMed Central, Dimensions, and EBSCO Host, using keywords such as coinfections, virus, viral hybrids, and superinfection. The articles pertinent to the concept were then included. Results: There is a growing body of evidence that suggests the formation of hybrid viral particles (HVPs) which conjugate at the cellular and subcellular level. While the formation of HVPs is bizarre, it may potentially have a profound effect on the clinical manifestations. Conclusion: While there has been evidence of the formation of HVPs between a couple of viruses, researchers fear the existence of several other combinations, including zoonotic viruses. While this could be detrimental to the human race both at an individual-as well as a community-level, an in-depth understanding of the same may help in better management of the clinical manifestations of the disease.
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The global epidemic of Sickle cell anemia (SCA) is causing thousands of children to die. SCA, a genetic disorder affecting the hemoglobin-globin chain, affects millions globally. The primary physiological issue in these patients is the polymerization of sickle hemoglobin within their red blood cells (RBCs) during their deoxygenating state. The RBC undergoes a sickle shape due to the polymerization of mutant hemoglobin within it and membrane deformation during anoxic conditions. To prevent complications, it is essential to effectively stop the sickling of RBCs of the patients. Various medications have been studied for treating SCA patients, focusing on antisickling, γ-globulin induction, and antiplatelet action. Natural and synthetic anti-sickling agents can potentially reduce patient clinical morbidity. Numerous clinical trials focused on using natural remedies for the symptomatic therapy of SCA. Medicinal plants and phytochemical agents have antisickling properties. Recent studies on plant extracts' natural compounds have primarily focused on in vitro RBCs sickling studies, with limited data on in vivo studies. This review discussed the potential role of phytoconstituents in the management of SCA.
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Anemia Falciforme , Antidrepanocíticos , Compostos Fitoquímicos , Extratos Vegetais , Anemia Falciforme/tratamento farmacológico , Humanos , Antidrepanocíticos/farmacologia , Antidrepanocíticos/uso terapêutico , Extratos Vegetais/farmacologia , Compostos Fitoquímicos/farmacologia , Fitoterapia , Hemoglobina Falciforme , Plantas Medicinais/química , Eritrócitos/efeitos dos fármacosRESUMO
Breast cancer has rapidly increased in prevalence in recent years, making it one of the leading causes of mortality worldwide. Among all cancers, it is by far the most common. Diagnosing this illness manually requires significant time and expertise. Since detecting breast cancer is a time-consuming process, preventing its further spread can be aided by creating machine-based forecasts. Machine learning and Explainable AI are crucial in classification as they not only provide accurate predictions but also offer insights into how the model arrives at its decisions, aiding in the understanding and trustworthiness of the classification results. In this study, we evaluate and compare the classification accuracy, precision, recall, and F1 scores of five different machine learning methods using a primary dataset (500 patients from Dhaka Medical College Hospital). Five different supervised machine learning techniques, including decision tree, random forest, logistic regression, naive bayes, and XGBoost, have been used to achieve optimal results on our dataset. Additionally, this study applied SHAP analysis to the XGBoost model to interpret the model's predictions and understand the impact of each feature on the model's output. We compared the accuracy with which several algorithms classified the data, as well as contrasted with other literature in this field. After final evaluation, this study found that XGBoost achieved the best model accuracy, which is 97%.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Teorema de Bayes , Bangladesh/epidemiologia , Mama , Aprendizado de Máquina , HidrolasesRESUMO
A neurodegenerative disorder (ND) refers to Huntington's disease (HD) which affects memory loss, weight loss, and movement dysfunctions such as chorea and dystonia. In the striatum and brain, HD most typically impacts medium-spiny neurons. Molecular genetics, excitotoxicity, oxidative stress (OS), mitochondrial, and metabolic dysfunction are a few of the theories advanced to explicit the pathophysiology of neuronal damage and cell death. Numerous in-depth studies of the literature have supported the therapeutic advantages of natural products in HD experimental models and other treatment approaches. This article briefly discusses the neuroprotective impacts of natural compounds against HD models. The ability of the discovered natural compounds to suppress HD was tested using either in vitro or in vivo models. Many bioactive compounds considerably lessened the memory loss and motor coordination brought on by 3-nitropropionic acid (3-NP). Reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and enhanced mitochondrial energy generation have profoundly decreased the biochemical change. It is significant since histology showed that therapy with particular natural compounds lessened damage to the striatum caused by 3-NP. Moreover, natural products displayed varying degrees of neuroprotection in preclinical HD studies because of their antioxidant and anti-inflammatory properties, maintenance of mitochondrial function, activation of autophagy, and inhibition of apoptosis. This study highlighted about the importance of bioactive compounds and their semi-synthetic molecules in the treatment and prevention of HD.
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Produtos Biológicos , Doença de Huntington , Fármacos Neuroprotetores , Ratos , Animais , Doença de Huntington/metabolismo , Ratos Wistar , Acetilcolinesterase , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Produtos Biológicos/uso terapêutico , Nitrocompostos/farmacologia , Propionatos/farmacologia , Propionatos/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Modelos Animais de DoençasRESUMO
Colorectal cancer is the second leading cause of cancer-related deaths. In 2018, there were an estimated 1.8 million cases, and this number is expected to increase to 2.2 million by 2030. Despite its prevalence, the current therapeutic option has a lot of side effects and limitations. Therefore, this study was designed to employ a computational approach for the identification of anti-cancer inhibitors against colorectal cancer using Resveratrol derivatives. Initially, the pass prediction spectrum of 50 derivatives was conducted and selected top seven compounds based on the maximum pass prediction score. After that, a comprehensive analysis, including Lipinski Rule, pharmacokinetics, ADMET profile study, molecular orbitals analysis, molecular docking, molecular dynamic simulations, and MM-PBSA binding free energy calculations. The reported binding affinity ranges of Resveratrol derivatives from molecular docking were -6.1 kcal/mol to -7.9 kcal/mol against the targeted receptor of human armadillo repeats domain of adenomatous polyposis coli (APC) (PDB ID: 3NMW). Specifically, our findings reported that two compounds [(03) Resveratrol 3-beta-mono-D-glucoside, and (29) Resveratrol 3-Glucoside] displayed the highest level of effectiveness compared to all other derivatives (-7.7 kcal/mol and -7.9 kcal/mol), and favorable drug-likeness, and exceptional safety profiles. Importantly, almost all the molecules were reported as free from toxic effects. Subsequently, molecular dynamic simulations conducted over 100ns confirmed the stability of the top two ligand-protein complexes. These findings suggest that Resveratrol derivatives may be effective drug candidate to manage the colorectal cancer. However, further experimental research, such as in vitro/in vivo studies, is essential to validate these computational findings and confirm their practical value.
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Alzheimer's disease (AD) has few effective treatment options and continues to be a major global health concern. AD is a neurodegenerative disease that typically affects elderly people. Alkaloids have potential sources for novel drug discovery due to their diverse chemical structures and pharmacological activities. Alkaloids, natural products with heterocyclic nitrogen-containing structures, are considered potential treatments for AD. This review explores the neuroprotective properties of alkaloids in AD, focusing on their ability to regulate pathways such as amyloid-beta aggregation, oxidative stress, synaptic dysfunction, tau hyperphosphorylation, and neuroinflammation. The FDA has approved alkaloids such as acetylcholinesterase inhibitors like galantamine and rivastigmine. This article explores AD's origins, current market medications, and clinical applications of alkaloids in AD therapy. This review explores the development of alkaloid-based drugs for AD, focusing on pharmacokinetics, blood-brain barrier penetration, and potential adverse effects. Future research should focus on the clinical evaluation of promising alkaloids, developing recently discovered alkaloids, and the ongoing search for novel alkaloids for medical treatment. A pharmaceutical option containing an alkaloid may potentially slow down the progression of AD while enhancing its symptoms. This review highlights the potential of alkaloids as valuable drug leads in treating AD, providing a comprehensive understanding of their mechanisms of action and therapeutic implications.
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Alcaloides , Doença de Alzheimer , Fármacos Neuroprotetores , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Estresse Oxidativo/efeitos dos fármacosRESUMO
In the present work, phytoconstituents from Citrus limon are computationally tested against SARS-CoV-2 target protein such as Mpro - (5R82.pdb), Spike - (6YZ5.pdb) &RdRp - (7BTF.pdb) for COVID-19. Docking was done by glide model, QikProp was performed by in silico ADMET screening & Prime MM-GB/SA modules were used to define binding energy. When compared with approved COVID-19 drugs such as Remdesivir, Ritonavir, Lopinavir, and Hydroxychloroquine, plant-based constituents such as Quercetin, Rutoside, Naringin, Eriocitrin, and Hesperidin. bind with significant G-scores to the active SARS-CoV-2 place. The constituents Rutoside and Eriocitrin were studied in each MD simulation in 100â ns against 3 proteins 5R82.pdb, 6YZ5.pdb and 7BTF.pdb.We performed an assay with significant natural compounds from contacts and in silico results (Rutin, Eriocitrin, Naringin, Hesperidin) using 3CL protease assay kit (B.11529 Omicron variant). This kit contained 3CL inhibitor GC376 as Control. The IC50 value of the test compound was found to be Rutin -17.50â µM, Eriocitrin-37.91â µM, Naringin-39.58â µM, Hesperidine-140.20â µM, the standard inhibitory concentration of GC376 was 38.64â µM. The phytoconstituents showed important interactions with SARS-CoV-2 targets, and potential modifications could be beneficial for future development.
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Coxiella burnetii, the causative agent of Q fever, is an intracellular pathogen posing a significant global public health threat. There is a pressing need for dependable and effective treatments, alongside an urgency for further research into the molecular characterization of its genome. Within the genomic landscape of Coxiella burnetii, numerous hypothetical proteins remain unidentified, underscoring the necessity for in-depth study. In this study, we conducted comprehensive in silico analyses to identify and prioritize potential hypothetical protein of Coxiella burnetii, aiming to elucidate the structure and function of uncharacterized protein. Furthermore, we delved into the physicochemical properties, localization, and molecular dynamics and simulations, and assessed the primary, secondary, and tertiary structures employing a variety of bioinformatics tools. The in-silico analysis revealed that the uncharacterized protein contains a conserved Mth938-like domain, suggesting a role in preadipocyte differentiation and adipogenesis. Subcellular localization predictions indicated its presence in the cytoplasm, implicating a significant role in cellular processes. Virtual screening identified ligands with high binding affinities, suggesting the protein's potential as a drug target against Q fever. Molecular dynamics simulations confirmed the stability of these complexes, indicating their therapeutic relevance. The findings provide a structural and functional overview of an uncharacterized protein from C. burnetii, implicating it in adipogenesis. This study underscores the power of in-silico approaches in uncovering the biological roles of uncharacterized proteins and facilitating the discovery of new therapeutic strategies. The findings provide valuable preliminary data for further investigation into the protein's role in adipogenesis.
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Adipogenia , Proteínas de Bactérias , Coxiella burnetii , Simulação de Dinâmica Molecular , Coxiella burnetii/metabolismo , Coxiella burnetii/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/química , Febre Q/microbiologia , HumanosRESUMO
The curry powder spices turmeric (Curcuma longa L.), which contains curcumin (diferuloylmethane), an orange-yellow chemical. Polyphenols are the most commonly used sources of curcumin. It combats oxidative stress and inflammation in diseases, such as hyperlipidemia, metabolic syndrome, arthritis, and depression. Most of these benefits are due to their anti-inflammatory and antioxidant properties. Curcumin consumption leads to decreased bioavailability, resulting in limited absorption, quick metabolism, and quick excretion, which hinders health improvement. Numerous factors can increase its bioavailability. Piperine enhances bioavailability when combined with curcumin in a complex. When combined with other enhancing agents, curcumin has a wide spectrum of health benefits. This review evaluates the therapeutic potential of curcumin with a specific emphasis on its approach based on molecular signaling pathways. This study investigated its influence on the progression of cancer, inflammation, and many health-related mechanisms, such as cell proliferation, apoptosis, and metastasis. Curcumin has a significant potential for the prevention and treatment of various diseases. Curcumin modulates several biochemical pathways and targets involved in cancer growth. Despite its limited tissue accumulation and bioavailability when administered orally, curcumin has proven useful. This review provides an in-depth analysis of curcumin's therapeutic applications, its molecular signaling pathway-based approach, and its potential for precision medicine in cancer and human health.
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Curcumina , Neoplasias , Humanos , Curcumina/farmacologia , Curcumina/uso terapêutico , Curcumina/química , Neoplasias/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Transdução de Sinais , Inflamação/tratamento farmacológicoRESUMO
BACKGROUND: Punica granatum L. is well-known for its multifaceted therapeutic potential, including anti-inflammatory and immunomodulatory activities. AIM: This study aimed to characterize an immunomodulatory compound isolated from Punica granatum L. using a bioactivity-guided approach. METHODS: Chromatographic techniques were adopted for isolation and purification of secondary metabolites. In silico, in vitro, and in vivo methods were performed to characterize the therapeutic potential of the isolated compound. RESULTS: Using preparative thin-layer chromatography, rosmarinic acid was isolated from F4 (column chromatography product obtained from a butanolic fraction of the extract). The impact of rosmarinic acid was assessed in rats using the neutrophil adhesion test, DTH response, and phagocytic index. In immunized rats, rosmarinic acid demonstrated significant immunomodulatory potential. Computational experiments, like molecular docking and molecular dynamics, were also conducted against two targeted receptors, Cereblon (PDB ID: 8AOQ) and human CD22 (PDB ID: 5VKM). Computational studies suggested that an increase in phagocytic index by rosmarinic acid could be attributed to inhibiting Cereblon and CD22. Pharmacokinetics and toxicity prediction also suggested the drug-likeness of rosmarinic acid. CONCLUSION: Rosmarinic acid is a potential candidate, but extensive research needs to be done to translate this molecule from bench to bedside.
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Atomoxetine is a drug widely used for the treatment of the attention deficit hyperactivity disorder (ADHD) with reduced risk of adverse motor reactions and chemical dependence. However, the pharmacokinetics characteristics as well as the toxicological risk of atomoxetine deserves further investigation to comprehensively analyze the therapeutic and safety aspects of this drug. This study aimed to predict the physicochemical profile and medicinal chemistry characteristics of atomoxetine, alongside its pharmacokinetic properties-namely absorption, distribution, metabolism, and excretion-as well as its toxicology (ADMET) potential through the utilization of web-based in silico tools. This research emphasizes predicted physicochemical, medicinal chemistry, and absorption parameters of atomoxetine that could influence the efficacy and safety of this drug for ADHD treatment. Additionally, atomoxetine also presents noteworthy predicted risks of hepatotoxicity, cardiotoxicity, neurotoxicity, nephrotoxicity, respiratory system toxicity, skin toxicity, and carcinogenicity. These findings underscore the necessity for further assessments of atomoxetine's safety profile, particularly considering different patient populations and durations of drug treatment. The data reported here from in silico predictions suggest that closer monitoring is warranted when atomoxetine is administered to patients with ADHD. Moreover, controlled studies detailing reliable protocols for personalized dosing, considering the multifactorial variability in metabolism efficiency and toxicological potential, would enable a more comprehensive assessment of atomoxetine's safety profile.
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Ebola virus disease (EVD) causes outbreaks and epidemics in West Africa that persist until today. The envelope glycoprotein of Ebola virus (GP) consists of two subunits, GP1 and GP2, and plays a key role in anchoring or fusing the virus to the host cell in its active form on the virion surface. Toremifene (TOR) is a ligand that mainly acts as an estrogen receptor antagonist; however, a recent study showed a strong and efficient interaction with GP. In this context, we aimed to evaluate the energetic affinity features involved in the interaction between GP and toremifene by computer simulation techniques using the Molecular Fractionation Method with Conjugate Caps (MFCC) scheme and quantum-mechanical (QM) calculations, as well as missense mutations to assess protein stability. We identified ASP522, GLU100, TYR517, THR519, LEU186, LEU515 as the most attractive residues in the EBOV glycoprotein structure that form the binding pocket. We divided toremifene into three regions and evaluated that region i was more important than region iii and region ii for the formation of the TOR-GP1/GP2 complex, which might control the molecular remodeling process of TOR. The mutations that caused more destabilization were ARG134, LEU515, TYR517 and ARG559, while those that caused stabilization were GLU523 and ASP522. TYR517 is a critical residue for the binding of TOR, and is highly conserved among EBOV species. Our results may help to elucidate the mechanism of drug action on the GP protein of the Ebola virus and subsequently develop new pharmacological approaches against EVD.Communicated by Ramaswamy H. Sarma.
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Yellow fever outbreaks are prevalent, particularly in endemic regions. Given the lack of an established treatment for this disease, significant attention has been directed toward managing this arbovirus. In response, we developed a multiepitope vaccine designed to elicit an immune response, utilizing advanced immunoinformatic and molecular modeling techniques. To achieve this, we predicted B- and T-cell epitopes using the sequences from all structural (E, prM, and C) and nonstructural proteins of 196 YFV strains. Through comprehensive analysis, we identified 10 cytotoxic T-lymphocyte (CTL) and 5T-helper (Th) epitopes that exhibited overlap with B-lymphocyte epitopes. These epitopes were further evaluated for their affinity to a wide range of human leukocyte antigen system alleles and were rigorously tested for antigenicity, immunogenicity, allergenicity, toxicity, and conservation. These epitopes were linked to an adjuvant ( ß -defensin) and to each other using ligands, resulting in a vaccine sequence with appropriate physicochemical properties. The 3D structure of this sequence was created, improved, and quality checked; then it was anchored to the Toll-like receptor. Molecular Dynamics and Quantum Mechanics/Molecular Mechanics simulations were employed to enhance the accuracy of docking calculations, with the QM portion of the simulations carried out utilizing the density functional theory formalism. Moreover, the inoculation model was able to provide an optimal codon sequence that was inserted into the pET-28a( +) vector for in silico cloning and could even stimulate highly relevant humoral and cellular immunological responses. Overall, these results suggest that the designed multi-epitope vaccine can serve as prophylaxis against the yellow fever virus.