Detailed Information on Publication Record
2021
Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance
MARQUES, Sérgio Manuel, Lucie ŠUPOLÍKOVÁ, Lenka MOLČANOVÁ, Karel ŠMEJKAL, David BEDNÁŘ et. al.Basic information
Original name
Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance
Authors
MARQUES, Sérgio Manuel (620 Portugal, belonging to the institution), Lucie ŠUPOLÍKOVÁ (203 Czech Republic, belonging to the institution), Lenka MOLČANOVÁ (703 Slovakia, belonging to the institution), Karel ŠMEJKAL (203 Czech Republic, belonging to the institution), David BEDNÁŘ (203 Czech Republic, belonging to the institution) and Iva SLANINOVÁ (203 Czech Republic, guarantor, belonging to the institution)
Edition
BIOMEDICINES, BASEL, MDPI, 2021, 2227-9059
Other information
Language
English
Type of outcome
Článek v odborném periodiku
Field of Study
30104 Pharmacology and pharmacy
Country of publisher
Switzerland
Confidentiality degree
není předmětem státního či obchodního tajemství
References:
Impact factor
Impact factor: 4.757
RIV identification code
RIV/00216224:14110/21:00121577
Organization unit
Faculty of Medicine
UT WoS
000642790800001
Keywords in English
flavonoids; molecular dynamics; molecular docking; multidrug resistance; natural compounds; P-glycoprotein; structure-based virtual screening
Tags
International impact, Reviewed
Změněno: 15/2/2023 23:15, Mgr. Michaela Hylsová, Ph.D.
Abstract
V originále
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.
Links
| LM2018121, research and development project |
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| LM2018131, research and development project |
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| LM2018140, research and development project |
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| MUNI/A/1325/2020, interní kód MU |
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| 814418, interní kód MU |
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