The aim of our study was to determine the PPARγ agonism and hypoglycemic activity of natural phenolics isolated from Paulownia tomentosa and Morus alba. We started with a molecular docking preselection, followed by in vitro cell culture assays, such as PPARγ luciferase reporter gene assay and PPARγ protein expression by Western blot analysis. The ability of the selected compounds to induce GLUT4 translocation in cell culture and lower blood glucose levels in chicken embryos was also determined. Among the thirty-six plant phenolic compounds, moracin M showed the highest hypoglycemic effect in an in ovo experiment (7.33 ± 2.37%), followed by mulberrofuran Y (3.84 ± 1.34%) and diplacone (3.69 ± 1.37%). Neither moracin M nor mulberrofuran Y showed a clear effect on the enhancement of GLUT4 translocation or agonism on PPARγ, while diplacone succeeded in both (3.62 ± 0.16% and 2.4-fold ± 0.2, respectively). Thus, we believe that the compounds moracin M, mulberrofuran Y, and diplacone are suitable for further experiments to elucidate their mechanisms of action.

• Klíčová slova
• PPARγ, diabetes mellitus, hypoglycemic, natural products, plant phenolics,
• MeSH
• fenoly * chemie   farmakologie   izolace a purifikace   MeSH
• hypoglykemika * chemie   farmakologie   izolace a purifikace   MeSH
• kuřecí embryo MeSH
• lidé MeSH
• Morus * chemie   MeSH
• myši MeSH
• PPAR gama * agonisté   metabolismus   genetika   chemie   MeSH
• přenašeč glukosy typ 4 metabolismus   genetika   MeSH
• rostlinné extrakty * chemie   farmakologie   izolace a purifikace   MeSH
• simulace molekulového dockingu MeSH
• zvířata MeSH
• Check Tag
• kuřecí embryo MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fenoly * MeSH
• hypoglykemika * MeSH
• PPAR gama * MeSH
• přenašeč glukosy typ 4 MeSH
• rostlinné extrakty * MeSH

Multidrug resistance (MDR) is a common problem when fighting cancer with chemotherapy. P-glycoprotein (P-gp, or MDR1) is an active pump responsible for the efflux of xenobiotics out of the cell, including anti-cancer drugs. It is a validated target against MDR. No crystal structure of the human P-gp is available to date, and only recently several cryo-EM structures have been solved. In this paper, we present a comprehensive computational approach that includes constructing the full-length three-dimensional structure of the human P-gp and its refinement using molecular dynamics. We assessed its flexibility and conformational diversity, compiling a dynamical ensemble that was used to dock a set of lignan compounds, previously reported as active P-gp inhibitors, and disclose their binding modes. Based on the statistical analysis of the docking results, we selected a system for performing the structure-based virtual screening of new potential P-gp inhibitors. We tested the method on a library of 87 natural flavonoids described in the literature, and 10 of those were experimentally assayed. The results reproduced the theoretical predictions only partially due to various possible factors. However, at least two of the predicted natural flavonoids were demonstrated to be effective P-gp inhibitors. They were able to increase the accumulation of doxorubicin inside the human promyelocytic leukemia HL60/MDR cells overexpressing P-gp and potentiate the antiproliferative activity of this anti-cancer drug.

• Klíčová slova
• P-glycoprotein, flavonoids, molecular docking, molecular dynamics, multidrug resistance, natural compounds, structure-based virtual screening,
• Publikační typ
• časopisecké články MeSH