title: Three-dimensional quantitative structure-activity relationship and docking studies in a series of anthocyanin derivatives as cytochrome P450 3A4 inhibitors.
abstract: 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 q (2) of 0.795 (0.687) and r (2) of 0.962 (0.948), respectively. The models were also validated by an external test set of four compounds with r (2) of 0.821 (CoMFA) and r (2) 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 r (2) 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.
authors.affiliation: Department of Anesthesia and Critical Care, University of Würzburg, Würzburg, Germany.
authors.forename: Sergey
authors.initials: S
authors.lastname: Shityakov
authors.affiliation: Cyclolab Cyclodextrin Research and Development Laboratory Ltd, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Puskás
authors.affiliation: Department of Anesthesia and Critical Care, University of Würzburg, Würzburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Roewer
authors.affiliation: Department of Anesthesia and Critical Care, University of Würzburg, Würzburg, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Förster
authors.affiliation: Department of Anesthesia and Critical Care, University of Würzburg, Würzburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Broscheit
keywords: anthocyanin derivatives; carcinogen activation; comparative molecular field analysis; comparative molecular similarity index analysis; cytochrome P450 3A4; molecular docking; three-dimensional quantitative structure–activity relationship
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