Publication details

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

Authors

MARQUES Sérgio Manuel ŠUPOLÍKOVÁ Lucie MOLČANOVÁ Lenka ŠMEJKAL Karel BEDNÁŘ David SLANINOVÁ Iva

Year of publication 2021
Type Article in Periodical
Magazine / Source BIOMEDICINES
MU Faculty or unit

Faculty of Medicine

Citation
Web https://www.mdpi.com/2227-9059/9/4/357
Doi http://dx.doi.org/10.3390/biomedicines9040357
Keywords flavonoids; molecular dynamics; molecular docking; multidrug resistance; natural compounds; P-glycoprotein; structure-based virtual screening
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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