RESUMO
Toll-like receptor 4 (TLR4) pathway is one of the major pathways that mediate the inflammation in human body. There are different anti-inflammatory drugs available in the market which specifically act on different signaling proteins of TLR4 pathway but they do have few side effects and other limitations for intended use in human body. In this study, Curcumin and its different analogs have been analyzed as the inhibitors of signaling proteins, i.e. Cycloxygenase-2 (COX-2), inhibitor of kappaß kinase (IKK) and TANK binding kinase-1 (TBK-1) of TLR4 pathway using different computational tools. Initially, three compounds were selected for respective target based on free binding energy among which different compounds were reported to have better binding affinity than commercially available drug (control). Upon continuous computational exploration with induced fit docking (IFD), 6-Gingerol, Yakuchinone A and Yakuchinone B were identified as the best inhibitors of COX-2, IKK, and TBK-1 respectively. Then their drug-like potentialities were analyzed in different experiments where they were also predicted to perform well. Hopefully, this study will uphold the efforts of researchers to identify anti-inflammatory drugs from natural sources.
Assuntos
Química Computacional , Curcumina/química , Inflamação/tratamento farmacológico , Receptor 4 Toll-Like/química , Catecóis/química , Catecóis/isolamento & purificação , Catecóis/uso terapêutico , Curcumina/análogos & derivados , Curcumina/isolamento & purificação , Curcumina/uso terapêutico , Ciclo-Oxigenase 2/genética , Diarileptanoides/química , Diarileptanoides/isolamento & purificação , Diarileptanoides/uso terapêutico , Álcoois Graxos/química , Álcoois Graxos/isolamento & purificação , Álcoois Graxos/uso terapêutico , Guaiacol/análogos & derivados , Guaiacol/química , Guaiacol/isolamento & purificação , Guaiacol/uso terapêutico , Humanos , Quinase I-kappa B/genética , Inflamação/genética , Lipopolissacarídeos/química , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Preparações Farmacêuticas/química , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genéticaRESUMO
The molecular mechanism of COVID-19's pathogenic effects in leukemia patients is still poorly known. Our study investigated the possible disease mechanism of COVID-19 and its associated risk factors in patients with leukemia utilizing differential gene expression analysis. We also employed network-based approaches to identify molecular targets that could potentially diagnose and treat COVID-19-infected leukemia patients. Our study demonstrated a shared set of 60 genes that are expressed differentially among patients with leukemia and COVID-19. Most of these genes are expressed in blood and bone marrow tissues and are predominantly implicated in the pathogenesis of different hematologic malignancies, increasingly imperiling COVID-19 morbidity and mortality among the affected patients. Additionally, we also found that COVID-19 may influence the expression of several cancer-associated genes in leukemia patients, such as CCR7, LEF1, and 13 candidate cancer-driver genes. Furthermore, our findings reveal that COVID-19 may predispose leukemia patients to altered blood homeostasis, increase the risk of COVID-19-related liver injury, and deteriorate leukemia-associated injury and patient prognosis. Our findings imply that molecular signatures, like transcription factors, proteins such as TOP21, and 25 different microRNAs, may be potential targets for diagnosing and treating COVID-19-infected leukemia patients. Nevertheless, additional experimental studies will contribute to further validating the study's findings.
Assuntos
COVID-19 , Leucemia , Humanos , COVID-19/genética , Perfilação da Expressão Gênica , Leucemia/genética , Biologia Computacional , Fatores de Risco , Expressão GênicaRESUMO
SARS Coronavirus-2 (SARS-CoV-2) pandemic has become a global issue which has raised the concern of scientific community to design and discover a counter-measure against this deadly virus. So far, the pandemic has caused the death of hundreds of thousands of people upon infection and spreading. To date, no effective vaccine is available which can combat the infection caused by this virus. Therefore, this study was conducted to design possible epitope-based subunit vaccines against the SARS-CoV-2 virus using the approaches of reverse vaccinology and immunoinformatics. Upon continual computational experimentation, three possible vaccine constructs were designed and one vaccine construct was selected as the best vaccine based on molecular docking study which is supposed to effectively act against the SARS-CoV-2. Thereafter, the molecular dynamics simulation and in silico codon adaptation experiments were carried out in order to check biological stability and find effective mass production strategy of the selected vaccine. This study should contribute to uphold the present efforts of the researches to secure a definitive preventative measure against this lethal disease.