RESUMO
Breast cancer (BC) is still one of the major issues in world health, especially for women, which necessitates innovative therapeutic strategies. In this study, we investigated the efficacy of retinoic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), which plays a crucial role in the biosynthesis and metabolism of oestrogen and thereby influences the progression of BC and, the main objective of this investigation is to identify the possible drug candidate against BC through computational drug design approach including PASS prediction, molecular docking, ADMET profiling, molecular dynamics simulations (MD) and density functional theory (DFT) calculations. The result has reported that total eight derivatives with high binding affinity and promising pharmacokinetic properties among 115 derivatives. In particular, ligands 04 and 07 exhibited a higher binding affinity with values of -9.9 kcal/mol and -9.1 kcal/mol, respectively, than the standard drug epirubicin hydrochloride, which had a binding affinity of -8.2 kcal/mol. The stability of the ligand-protein complexes was further confirmed by MD simulations over a 100-ns trajectory, which included assessments of hydrogen bonds, root mean square deviation (RMSD), root mean square Fluctuation (RMSF), dynamic cross-correlation matric (DCCM) and principal component analysis. The study emphasizes the need for experimental validation to confirm the therapeutic utility of these compounds. This study enhances the computational search for new BC drugs and establishes a solid foundation for subsequent experimental and clinical research.
Assuntos
Neoplasias da Mama , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Feminino , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ligantes , Simulação por Computador , Ligação Proteica , Tretinoína/metabolismo , Desenho de Fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , 17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 17-Hidroxiesteroide Desidrogenases/metabolismo , 17-Hidroxiesteroide Desidrogenases/química , Ligação de HidrogênioRESUMO
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.
Assuntos
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
Diabetic neuropathic pain is one of the most devasting disorders of peripheral nervous system. The loss of GABAergic inhibition is associated with the development of painful diabetic neuropathy. The current study evaluated the potential of 3-Hydroxy-2-methoxy-6-methyl flavone (3-OH-2'MeO6MF), to ameliorate peripheral neuropathic pain using an STZ-induced hyperglycemia rat model. The pain threshold was assessed by tail flick, cold, mechanical allodynia, and formalin test on days 0, 14, 21, and 28 after STZ administration accompanied by evaluation of several biochemical parameters. Administration of 3-OH-2'-MeO6MF (1,10, 30, and 100 mg/kg, i.p) significantly enhanced the tail withdrawal threshold in tail-flick and tail cold allodynia tests. 3-OH-2'-MeO6MF also increased the paw withdrawal threshold in mechanical allodynia and decreased paw licking time in the formalin test. Additionally, 3-OH-2'-MeO6MF also attenuated the increase in concentrations of myeloperoxidase (MPO), thiobarbituric acid reactive substances (TBARS), nitrite, TNF-α, and IL 6 along with increases in glutathione (GSH). Pretreatment of pentylenetetrazole (PTZ) (40 mg/kg, i.p.) abolished the antinociceptive effect of 3-OH-2'-MeO6MF in mechanical allodynia. Besides, the STZ-induced alterations in the GABA concentration and GABA transaminase activity attenuated by 3-OH-2'-MeO6MF treatment suggest GABAergic mechanisms. Molecular docking also authenticates the involvement of α2ß2γ2L GABA-A receptors and GABA-T enzyme in the antinociceptive activities of 3-OH-2'-MeO6MF.
Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Flavonas , Neuralgia , Ratos , Animais , Hiperalgesia/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Estreptozocina , Simulação de Acoplamento Molecular , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/complicações , Analgésicos/farmacologia , Ácido gama-Aminobutírico/farmacologia , Flavonas/farmacologia , Flavonas/uso terapêutico , BiomarcadoresRESUMO
BACKGROUND: Oral health remains a significant global concern with the prevalence of oral pathogens and the increasing incidence of oral cancer posing formidable challenges. Additionally, the emergence of antibiotic-resistant strains has complicated treatment strategies, emphasizing the urgent need for alternative therapeutic approaches. Recent research has explored the application of plant compounds mediated with nanotechnology in oral health, focusing on the antimicrobial and anticancer properties. METHODS: In this study, curcumin (Cu)-mediated zinc oxide nanoparticles (ZnO NPs) were synthesized and characterized using SEM, EDAX, UV spectroscopy, FTIR, and XRD to validate their composition and structural features. The antioxidant and antimicrobial activity of ZnO-CU NPs was investigated through DPPH, ABTS, and zone of inhibition assays. Apoptotic assays and gene expression analysis were performed in KB oral squamous carcinoma cells to identify their anticancer activity. RESULTS: ZnO-CU NPs showcased formidable antioxidant prowess in both DPPH and ABTS assays, signifying their potential as robust scavengers of free radicals. The determined minimal inhibitory concentration of 40 µg/mL against dental pathogens underscored the compelling antimicrobial attributes of ZnO-CU NPs. Furthermore, the interaction analysis revealed the superior binding affinity and intricate amino acid interactions of ZnO-CU NPs with receptors on dental pathogens. Moreover, in the realm of anticancer activity, ZnO-CU NPs exhibited a dose-dependent response against Human Oral Epidermal Carcinoma KB cells at concentrations of 10 µg/mL, 20 µg/mL, 40 µg/mL, and 80 µg/mL. Unraveling the intricate mechanism of apoptotic activity, ZnO-CU NPs orchestrated the upregulation of pivotal genes, including BCL2, BAX, and P53, within the KB cells. CONCLUSIONS: This multifaceted approach, addressing both antimicrobial and anticancer activity, positions ZnO-CU NPs as a compelling avenue for advancing oral health, offering a comprehensive strategy for tackling both oral infections and cancer.
Assuntos
Anti-Infecciosos , Benzotiazóis , Carcinoma de Células Escamosas , Curcumina , Nanopartículas Metálicas , Neoplasias Bucais , Ácidos Sulfônicos , Óxido de Zinco , Humanos , Óxido de Zinco/farmacologia , Óxido de Zinco/química , Curcumina/farmacologia , Nanopartículas Metálicas/química , Antioxidantes/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Biofilmes , Extratos Vegetais/química , Testes de Sensibilidade MicrobianaRESUMO
It is now widely accepted that inflammation is critical in cardiovascular diseases (CVD). Here, studies are being conducted on how cyclic GMP-AMP synthase (cGAS), a component of innate immunity's DNA-sensing machinery, communicates with the STING receptor, which is involved in activating the immune system's antiviral response. Significantly, a growing body of research in recent years highlights the strong activation of the cGAS-STING signalling pathways in several cardiovascular diseases, such as myocardial infarction, heart failure, and myocarditis. This developing collection of research emphasises these pathways' crucial role in initiating and advancing cardiovascular disease. In this extensive narrative, we explore the role of the cGAS-STING pathway in the development of CVD. We elaborate on the basic mechanisms involved in the onset and progression of CVD. This review explores the most recent developments in the recognition and characterization of cGAS-STING pathway. Additionally, it considers the field's future prospects while examining how cGAS-STING pathway might be altered and its clinical applications for cardiovascular diseases.
Assuntos
Doenças Cardiovasculares , Humanos , Progressão da Doença , Inflamação , Nucleotidiltransferases/metabolismo , Transdução de Sinais/fisiologiaRESUMO
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.
RESUMO
Listeria monocytogenes is an important food-borne pathogen that causes listeriosis and has a high case fatality rate despite its low incidence. Medicinal plants and their secondary metabolites have been identified as potential antibacterial substances, serving as replacements for synthetic chemical compounds. The present studies emphasize two significant medicinal plants, Allium cepa and Zingiber officinale, and their efficacy against L. monocytogenes. Firstly, a bacterial isolate was obtained from milk and identified through morphology and biochemical reactions. The species of the isolate were further confirmed through 16S rRNA analysis. Furthermore, polar solvents such as methanol and ethanol were used for the extraction of secondary metabolites from A. cepa and Z. officinale. Crude phytochemical components were identified using phytochemical tests, FTIR, and GC-MS. Moreover, the antibacterial activity of the crude extract and its various concentrations were tested against L. monocytogenes. Among all, A. cepa in methanolic extracts showed significant inhibitory activity. Since, the A. cepa for methanolic crude extract was used to perform autography to assess its bactericidal activity. Subsequently, molecular docking was performed to determine the specific compound inhibition. The docking results revealed that four compounds displayed strong binding affinity with the virulence factor Listeriolysin-O of L. monocytogenes. Based on the above results, it can be concluded that the medicinal plant A. cepa has potential antibacterial effects against L. monocytogenes, particularly targeting its virulence.