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@article{1768219,
author = {Marques, Sérgio Manuel and Šupolíková, Lucie and Molčanová, Lenka and Šmejkal, Karel and Bednář, David and Slaninová, Iva},
article_location = {BASEL},
article_number = {4},
doi = {http://dx.doi.org/10.3390/biomedicines9040357},
keywords = {flavonoids; molecular dynamics; molecular docking; multidrug resistance; natural compounds; P-glycoprotein; structure-based virtual screening},
language = {eng},
issn = {2227-9059},
journal = {BIOMEDICINES},
title = {Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance},
url = {https://www.mdpi.com/2227-9059/9/4/357},
volume = {9},
year = {2021}
}
TY - JOUR
ID - 1768219
AU - Marques, Sérgio Manuel - Šupolíková, Lucie - Molčanová, Lenka - Šmejkal, Karel - Bednář, David - Slaninová, Iva
PY - 2021
TI - Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance
JF - BIOMEDICINES
VL - 9
IS - 4
SP - 1-22
EP - 1-22
PB - MDPI
SN - 22279059
KW - flavonoids
KW - molecular dynamics
KW - molecular docking
KW - multidrug resistance
KW - natural compounds
KW - P-glycoprotein
KW - structure-based virtual screening
UR - https://www.mdpi.com/2227-9059/9/4/357
N2 - 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.
ER -
MARQUES, Sérgio Manuel, Lucie ŠUPOLÍKOVÁ, Lenka MOLČANOVÁ, Karel ŠMEJKAL, David BEDNÁŘ and Iva SLANINOVÁ. Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance. \textit{BIOMEDICINES}. BASEL: MDPI, 2021, vol.~9, No~4, p.~1-22. ISSN~2227-9059. Available from: https://dx.doi.org/10.3390/biomedicines9040357.
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