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Article

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

1
Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Kamenice 5/C13, 625-00 Brno, Czech Republic
2
International Clinical Research Center, St. Anne’s University Hospital Brno, Pekarska 53, 656-91 Brno, Czech Republic
3
Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5/A6, 625-00 Brno, Czech Republic
4
Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Palackého 1946/1, 612-00 Brno, Czech Republic
*
Authors to whom correspondence should be addressed.
Academic Editor: Marek Drozdzik
Biomedicines 2021, 9(4), 357; https://doi.org/10.3390/biomedicines9040357
Received: 9 March 2021 / Revised: 25 March 2021 / Accepted: 26 March 2021 / Published: 30 March 2021
(This article belongs to the Special Issue Drug Transporters)
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. View Full-Text
Keywords: flavonoids; molecular dynamics; molecular docking; multidrug resistance; natural compounds; P-glycoprotein; structure-based virtual screening flavonoids; molecular dynamics; molecular docking; multidrug resistance; natural compounds; P-glycoprotein; structure-based virtual screening
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MDPI and ACS Style

Marques, S.M.; Šupolíková, L.; Molčanová, L.; Šmejkal, K.; Bednar, D.; Slaninová, I. Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance. Biomedicines 2021, 9, 357. https://doi.org/10.3390/biomedicines9040357

AMA Style

Marques SM, Šupolíková L, Molčanová L, Šmejkal K, Bednar D, Slaninová I. Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance. Biomedicines. 2021; 9(4):357. https://doi.org/10.3390/biomedicines9040357

Chicago/Turabian Style

Marques, Sérgio M., Lucie Šupolíková, Lenka Molčanová, Karel Šmejkal, David Bednar, and Iva Slaninová. 2021. "Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance" Biomedicines 9, no. 4: 357. https://doi.org/10.3390/biomedicines9040357

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