Quantitative Structure–Activity Relationships for the Flavonoid-Mediated Inhibition of P-Glycoprotein in KB/MDR1 Cells

Abstract

P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance (MDR) in cancer cells. In order to enhance the uptake of chemotherapy drugs, larger amounts of P-gp inhibitors are required. Besides several chemically synthesized P-gp inhibitors, flavonoids as P-gp inhibitors are being investigated, with their advantages including abundance in our daily diet and a low toxicity. The cytotoxicity of daunorubicin (as a substrate of P-gp) to KB/MDR1 cells and the parental KB cells was measured in the presence or absence of flavonoids. A two-dimensional quantitative structure–activity relationship (2D-QSAR) model was built with a high cross-validation coefficient (Q2) value of 0.829. Descriptors including vsurf_DW23, E_sol, Dipole and vsurf_G were determined to be related to the inhibitory activity of flavonoids. The lack of 2,3-double bond, 3′-OH, 4′-OH and the increased number of methoxylated substitutions were shown to be beneficial for the inhibition of P-gp. These results are important for the screening of flavonoids for inhibitory activity on P-gp.

A Novel Dual Drug Approach That Combines Ivermectin and Dihydromyricetin (DHM) to Reduce Alcohol Drinking and Preference in Mice

“…Our results demonstrate that 2,3-saturation and 4-carbonyl of both DHM and taxifolin are involved in key ligand-residue interactions and support DHM as a Pgp ATPase inhibitor. The involvement of 2,3-saturation in binding pocket interactions correlates with SAR studies associating 2,3-saturation with enhanced potency of Pgp inhibition [ 35 ]. As SAR studies are reported for flavonoids similar to DHM, these data, coupled with modeling studies, could be utilized to guide the design of DHM analogs aimed at enhancing Pgp inhibition.…”

“…In addition, recent studies have shown that DHM can enhance the bioavailability of xenobiotic substrates of Pgp, suggesting that DHM acts as a Pgp inhibitor alongside other mechanisms that modify xenobiotic PK profiles [ 32 , 33 , 34 ]. Although the mechanism(s) associated with DHM’s ability to inhibit Pgp are unclear, recent structure-activity relationship (SAR) studies of flavonols and Pgp activity indicate that structural components of DHM are consistent with potent non-competitive Pgp inhibition of ATP hydrolysis [ 35 ]. For example, the 3′-OH, 4′-OH, and 2,3-saturation of DHM are associated with enhanced non-competitive Pgp inhibition [ 33 , 36 , 37 ].…”

Chemical molecular‐based approach to overcome multidrug resistance in cancer by targeting P‐glycoprotein (P‐gp)

“…Virtual screening can reduce the high cost of drug development and accelerate the discovery of lead compounds and drug candidates. Ligand‐based methods, such as QSAR 152 models, structure‐based approaches such as molecular dynamics and docking 153 and hierarchical cluster analysis 154 could be rational choices as tools for the design of P‐gp inhibitors with high potency. In particular, structure‐based modeling has gained more attention due to the increasing identification of 3D structures of P‐gp.…”

P-glycoprotein: new insights into structure, physiological function, regulation and alterations in disease

“…Such conflicting evidence prevent drugs from proceeding to the later phases of clinical trials and very few receive FDA approval due to reports of poor efficiency and high toxicity levels. The current known computational methods of predicting drug-protein interactions include quantitative structure activity relationship [ 281 ], classification models [ 282 ], and molecular docking [ 283 ], to name a few. Our current knowledge of the PGP structure, will tremendously aid this process as several of these methods rely on the accuracy of the three-dimensional structure of the protein.…”