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

Abstract

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.

Phytol and Heptacosane Are Possible Tools to Overcome Multidrug Resistance in an In Vitro Model of Acute Myeloid Leukemia

“…Some natural products extracted from plants, have been studied for their modulatory properties on P-gp in the form of alkaloids, flavonoids and phenolics, coumarins, resins, peptides, saponins, terpenoids, and miscellaneous other chemical species [ 8 , 43 , 44 ]. In vitro evidence has shown that some natural products, such as curcuminoids, ursolic and oleanolic acid, and essential oils, can counteract the phenomena of drug resistance in tumor models of innate and acquired resistance such as triple negative breast cancer, hepatocellular carcinoma, and acute myeloid leukemia [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. In this context, a recent paper has shown how essential oils are able to bypass multidrug resistance through different mechanisms all converging towards the inhibition of P-gp.…”

Reduction of breast tumor drug resistance by 2,3,5,4’-tetrahydroxystilbene for exhibition synergic chemotherapeutic effect

“…TG1 was derived from THSG deglucosylation, and it has a chemical structure with multiple hydroxyl groups. Previous study indicated that hydrogen bonds were formed between the hydroxyl groups of inhibitors and the R site of drug efflux pump, P-gp [ 27 ]. Thus, the modification of THSG may have improved the reduction of drug efflux effect via P-gp.…”

“…Furthermore, many researches were investigated resveratrol as a P-gp inhibitor on cancer cells overexpressing P-gp [ 42 – 44 ]. Since TG1 has similar chemical structure with resveratrol, and the potential P-gp inhibitor could be predicted by structure [ 27 ]. TG1 might be a P-gp inhibitor to modulate DTX/DOX resistance effects, but it needs more investigation in the future.…”

Generation of a Novel High-Affinity Antibody Binding to PCSK9 Catalytic Domain with Slow Dissociation Rate by CDR-Grafting, Alanine Scanning and Saturated Site-Directed Mutagenesis for Favorably Treating Hypercholesterolemia

“…We have also previously developed a human mAb targeting the C-terminal domain (CTD) of PCSK9 utilizing phage display-based strategy [ 29 ]. Molecular modeling and docking techniques are widely used to predict the binding mode of a drug with its protein target [ 68 , 69 ].…”