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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F21%3A00075131" target="_blank" >RIV/00159816:_____/21:00075131 - isvavai.cz</a>

Alternative codes found

RIV/00216224:14110/21:00121577

Result on the web

<a href="https://www.mdpi.com/2227-9059/9/4/357/htm" target="_blank" >https://www.mdpi.com/2227-9059/9/4/357/htm</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/biomedicines9040357" target="_blank" >10.3390/biomedicines9040357</a>

Result language

angličtina

Original language name

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

Original language 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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2021

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

BIOMEDICINES

ISSN

2227-9059

e-ISSN

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Volume of the periodical

9

Issue of the periodical within the volume

4

Country of publishing house

CH - SWITZERLAND

Number of pages

22

Pages from-to

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UT code for WoS article

000642790800001

EID of the result in the Scopus database

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