Three-dimensional quantitative structure–activity relationship and docking studies in a series of anthocyanin derivatives as cytochrome P450 3A4 inhibitors

Abstract

Sergey Shityakov,1 István Puskás,2 Norbert Roewer,1 Carola Förster,1 Jens Broscheit11Department of Anesthesia and Critical Care, University of Würzburg, Würzburg, Germany; 2CycloLab Cyclodextrin Research and Development Laboratory Ltd, Budapest, HungaryAbstract: The cytochrome P450 (CYP)3A4 enzyme affects the metabolism of most drug-like substances, and its inhibition may influence drug safety. Modulation of CYP3A4 by flavonoids, such as anthocyanins, has been shown to inhibit the mutagenic activity of mammalian cells. Considering the previous investigations addressing CYP3A4 inhibition by these substances, we studied the three-dimensional quantitative structure–activity relationship (3D-QSAR) in a series of anthocyanin derivatives as CYP3A4 inhibitors. For the training dataset (n=12), comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) yielded crossvalidated and non-crossvalidated models with a q2 of 0.795 (0.687) and r2 of 0.962 (0.948), respectively. The models were also validated by an external test set of four compounds with r2 of 0.821 (CoMFA) and r2 of 0.812 (CoMSIA). The binding affinity modes associated with experimentally derived IC50 (half maximal inhibitory concentration) values were confirmed by molecular docking into the CYP3A4 active site with r2 of 0.66. The results obtained from this study are useful for a better understanding of the effects of anthocyanin derivatives on inhibition of carcinogen activation and cellular DNA damage.Keywords: three-dimensional quantitative structure–activity relationship, cytochrome P450 3A4, comparative molecular field analysis, comparative molecular similarity index analysis, anthocyanin derivatives, molecular docking, carcinogen activation