3D-QSAR analysis of the interactions of flavonoids with human organic cation transporter 2

Flavonoids are a class of phenolic and polyphenolic compounds widely distributed in vegetables, fruits, grains and herbs. Organic cation transporter 2 (OCT2) mediates the renal secretion of organic cations and is a key site of drug-drug interactions (DDIs). In this study, we systematically investigated the inhibitory effect of 28 flavonoids on OCT2-mediated uptake of 4-4-dimethylaminostyryl-N-methylpyridinium (ASP(+)). Among them, scullcap-flavone II demonstrated the strongest inhibitory effect on OCT2-mediated uptake of ASP+ (IC50 =11.2 mu M) in a competitive manner. Next, 3D-QSAR analyses of flavonoid OCT2 inhibitors were performed using both CoMFA and CoMSIA models. The date revealed that bulky substituents at the C-3 and C-4 positions of ring C as well as the C-7 position of ring A could prevent the interactions of flavonoids with OCT2. In contrast, a hydrophilic and negatively charge substituent on ring A was favorable for the interactions of flavonoids with OCT2. Conse-quently, baicalin (IC50 =220.2 mu M) with a uronic acid substituent on ring A exhibited a stronger inhibition than baicalein (IC50 =294.5 mu M); quercetin-3-O-galactoside (IC50 =497.4 mu M) was a stronger inhibitor of OCT2 than rhamnetin 3-galactoside (IC50 =1409.0 mu M). Taken together, our findings could be valuable in elucidating and predicting the interactions of flavonoids with OCT2.

Automated summary

Flavonoids, widely found in vegetables, fruits, grains, and herbs, exhibit inhibitory effects on the organic cation transporter 2 (OCT2) which plays a crucial role in drug-drug interactions. This study investigated the inhibitory effect of 28 flavonoids on OCT2 and revealed the structural features that affect their interaction. The findings provide valuable insights into the interactions and prediction of flavonoids with OCT2.