A combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature

Abstract

The human cytochrome P450 2D6 (CYP2D6) enzyme is part of phase-I metabolism and metabolizes at least 20% of all clinically relevant drugs. Therefore, it is an important target for drug-drug interaction (DDI) studies. High-throughput screening (HTS) assays are commonly used tools to examine DDI, but show certain drawbacks with regard to their applicability to natural products. We propose an in silico – in vitro workflow for the reliable identification of natural products with CYP2D6 inhibitory potential. In order to identify candidates from natural product-based databases that share similar structural features with established inhibitors, a pharmacophore model was applied. The virtual hits were tested for the inhibition of recombinant human CYP2D6 in a bioluminescence-based assay. By controlling for unspecific interferences of the test compounds with the detection reaction, the number of false positives were reduced. The success rate of the reported workflow was 76%, as most of the candidates identified in the in silico approach were able to inhibit CYP2D6 activity. In summary, the workflow presented here is a suitable and cost-efficient strategy for the discovery of new CYP2D6 inhibitors with natural product libraries.

Design, Synthesis, Docking, Antitumor Screening, and Absorption, Distribution, Metabolism, and Excretion Prediction of New Hesperdin Derivative

“…The CYP2D6 model predicts the suppression and non-suppression performance of chemical structure and provides metabolic profile information. CYP2D6 enzyme plays important role in the metabolism of xenobiotic excretion from the body [15]. The result of the present study indicated that the new synthesized compound is non-suppression of CYP2D6; hence, its liver dysfunction effect is low.…”

Biotransformation, Using Recombinant CYP450-Expressing Baker’s Yeast Cells, Identifies a Novel CYP2D6.10A122V Variant Which Is a Superior Metabolizer of Codeine to Morphine Than the Wild-Type Enzyme

“…Several site-directed mutagenesis and computational studies on the CYP2D6 cDNA and protein, respectively, have demonstrated that Glu 216, Asp 301, Phe 120, and Met 374 are key determinants of substrate specificity and product regioselectivity in CYP2D6. 28 Because of the significant contribution of CYP2D6 in the metabolism of drugs, discovery of its inhibitors is a key research area in drug discovery programs. 28d Furthermore, the CYP2D6 enzyme has extensively been studied for delineation of the metabolism (O-demethylation and N-demethylation) of approved drugs viz metoprolol, 29 gefitinib, 30 and natural products.…”

In Silico Prediction of Drug–Drug Interactions Mediated by Cytochrome P450 Isoforms

“…A recently presented machine learning (ML) method used different molecular fingerprints to classify compounds as inhibitors or noninhibitors of five major cytochrome P450 isoenzymes [ 4 ]. Ligand-based and structure-based methods dealing with substrates, inhibitors [ 5 , 6 ], and inducers [ 7 ] of particular DMEs. Results of prediction could help to determine possible DDIs.…”