Epicatechin (EC) is a flavanol that has shown numerous biological effects such as: decrease risk of cardiovascular dysfunction, metabolism regulation, skeletal muscle (SkM) performance improvement and SkM cells differentiation induction, among others. The described EC acceptor/receptor molecules do not explain the EC's effect on SkM. We hypothesize that the pregnane X receptor (PXR) can fulfill those characteristics, based on structural similitude between EC and steroidal backbone and that PXR activation leads to similar effects as those induced by EC. In order to demonstrate our hypothesis, we: 1) analyzed the possible EC and mouse PXR interaction through in silico strategies, 2) developed an EC's affinity column to isolate PXR, 3) evaluated, in mouse myoblast (C2C12 cells) the inhibition of EC-induced PXR's nucleus translocation by ketoconazole, a specific blocker of PXR and 4) analyzed the effect of EC as an activator of mouse PXR, evaluating the expression modulation of cytochrome 3a11 (Cyp3a11) gen and myogenin protein. (-)-Epicatechin interacts and activates PXR, promoting this protein translocation to the nucleus, increasing the expression of Cyp3a11, and promoting C2C12 cell differentiation through increasing myogenin expression. These results can be the base of further studies to analyze the possible participation of PXR in the skeletal muscle effects shown by EC.
Despite the development of vaccines against COVID-19 disease and the multiple efforts to find efficient drugs as treatment for this virus, there are too many social, political, economic, and health inconveniences to incorporate a fully accessible plan of prevention and therapy against SARS-CoV-2. In this sense, it is necessary to find nutraceutical/pharmaceutical drugs as possible COVID-19 preventives/treatments. Based on their beneficial effects, flavonoids are one of the most promising compounds. Therefore, using virtual screening, 478 flavonoids obtained from the KEGG database were evaluated against non-structural proteins Nsp1, Nsp3, Nsp5, Nsp12, and Nsp15, which are essential for the virus-host cell infection, searching for possible multitarget flavonoids. Amentoflavone, a biflavonoid found mainly in Ginkgo biloba , Lobelia chinensis , and Byrsonima intermedia , can interact and bind with the five proteins, suggesting its potential as a multitarget inhibitor. Molecular docking calculations and structural analysis (RMSD, number of H bonds, and clustering) performed from molecular dynamics simulations of the amentoflavone-protein complex support this potential. The results shown here are theoretical evidence of the probable multitarget inhibition of non-structural proteins of SARS-CoV-2 by amentoflavone, which has wide availability, low cost, no side effects, and long history of use. These results are solid evidence for future in vitro and in vivo experiments aiming to validate amentoflavone as an inhibitor of the Nsp1, 3, 5, 12, and 15 of SARS-CoV-2. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00894-022-05391-6.
Existen varias teorías sobre cómo un fármaco interactúa con un receptor. Esta revisión muestra las teorías que se consideran más relevantes para dilucidar los mecanismos que rigen las interacciones fármaco-receptor, como la propuesta por A.J. Clark, quien establece que las interacciones fármacoreceptor pueden interpretarse como procesos que obedecen las leyes de la física y la química, y establece por primera vez un enfoque matemático que describe el comportamiento de una interacción ligando-receptor, este modelo se conoce como teoría ocupacional. Sin embargo, esta teoría se ha modificado con el desarrollo de nuevas tecnologías, como la tecnología recombinante, la cristalización de proteínas y las metodologías in silico, que contribuyen con importantes datos experimentales para comprender la interacción ligando-receptor. De esta manera, las teorías de interacciones fármaco-receptor se volvieron más complejas, precisas y obtuvieron algunos parámetros fundamentales como potencia, eficacia, dosis, tipos de agonismo (parcial, total, inverso), antagonismo (competitivo y no competitivo) o modulación. Es por esto que la implementación de estos nuevos conceptos en la farmacología de las teorías fármaco-receptor en el área clínica puede marcar la diferencia entre el éxito o el fracaso en el tratamiento farmacológico.
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