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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8066904 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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