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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 a Iva SLANINOVÁ. Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance. \textit{BIOMEDICINES}. BASEL: MDPI, 2021, roč.~9, č.~4, s.~1-22. ISSN~2227-9059. Dostupné z: https://dx.doi.org/10.3390/biomedicines9040357.
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