In Silico Prediction of Cytochrome P450-Drug Interaction: QSARs for CYP3A4 and CYP2C9.
Cytochromes P450 (CYP) are the main actors in the oxidation of xenobiotics and play a crucial role in drug safety, persistence, bioactivation, and drug-drug/food-drug interaction. This work aims to develop Quantitative Structure-Activity Relationship (QSAR) models to predict the drug interaction with two of the most important CYP isoforms, namely 2C9 and 3A4. The presented models are calibrated on 9122 drug-like compounds, using three different modelling approaches and two types of molecular description (classical molecular descriptors and binary fingerprints). For each isoform, three classification models are presented, based on a different approach and with different advantages: (1) a very simple and interpretable classification tree; (2) a local (k-Nearest Neighbor) model based classical descriptors and; (3) a model based on a recently proposed local classifier (N-Nearest Neighbor) on binary fingerprints. The salient features of the work are (1) the thorough model validation and the applicability domain assessment; (2) the descriptor interpretation, which highlighted the crucial aspects of P450-drug interaction; and (3) the consensus aggregation of models, which largely increased the prediction accuracy.
Department of Earth and Environmental Sciences, University of Milano-Bicocca, P.za della Scienza 1, 20126 Milano, Italy. s.nembri@campus.unimib.it.
Serena
S
Nembri
Department of Earth and Environmental Sciences, University of Milano-Bicocca, P.za della Scienza 1, 20126 Milano, Italy. f.grisoni@campus.unimib.it.
Francesca
F
Grisoni
Department of Earth and Environmental Sciences, University of Milano-Bicocca, P.za della Scienza 1, 20126 Milano, Italy. viviana.consonni@campus.unimib.it.
Viviana
V
Consonni
Department of Earth and Environmental Sciences, University of Milano-Bicocca, P.za della Scienza 1, 20126 Milano, Italy. roberto.todeschini@unimib.it.
Roberto
R
Todeschini
D000818:Animals; D003198:Computer Simulation; D065729:Cytochrome P-450 CYP2C9 / Q000737:chemistry* / Q000378:metabolism; D065688:Cytochrome P-450 CYP2C9 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry* / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
D065688:Cytochrome P-450 CYP2C9 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A
ADMET; CYP2C9; CYP3A4; QSAR; cytochrome P450; in silico