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Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance

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...

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Autores principales: Marques, Sérgio M., Šupolíková, Lucie, Molčanová, Lenka, Šmejkal, Karel, Bednar, David, Slaninová, Iva
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066904/
https://www.ncbi.nlm.nih.gov/pubmed/33808505
http://dx.doi.org/10.3390/biomedicines9040357
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author Marques, Sérgio M.
Šupolíková, Lucie
Molčanová, Lenka
Šmejkal, Karel
Bednar, David
Slaninová, Iva
author_facet Marques, Sérgio M.
Šupolíková, Lucie
Molčanová, Lenka
Šmejkal, Karel
Bednar, David
Slaninová, Iva
author_sort Marques, Sérgio M.
collection PubMed
description 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.
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spelling pubmed-80669042021-04-25 Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance Marques, Sérgio M. Šupolíková, Lucie Molčanová, Lenka Šmejkal, Karel Bednar, David Slaninová, Iva Biomedicines Article 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. MDPI 2021-03-30 /pmc/articles/PMC8066904/ /pubmed/33808505 http://dx.doi.org/10.3390/biomedicines9040357 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Marques, Sérgio M.
Šupolíková, Lucie
Molčanová, Lenka
Šmejkal, Karel
Bednar, David
Slaninová, Iva
Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance
title Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance
title_full Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance
title_fullStr Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance
title_full_unstemmed Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance
title_short Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance
title_sort screening of natural compounds as p-glycoprotein inhibitors against multidrug resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066904/
https://www.ncbi.nlm.nih.gov/pubmed/33808505
http://dx.doi.org/10.3390/biomedicines9040357
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