In Silico Modeling of P450 Substrates, Inhibitors, Activators, and Inducers

Abstract

Cytochrome P450 enzymes are the predominant mediators of phase I metabolism of exogenous small molecules. As a result of their extensive role in metabolism of xenobiotics, drug compounds, and endogenous compounds, as well as their wide tissue distribution, significant drug discovery resources are spent to avoid interacting with this class of enzymes. Here we review historical and recent in silico modeling of 7 cytochrome P450 enzymes of particular interest, specifically CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. For each we provide a brief biological background including known inhibitors, substrates, and inducers, as well as details of computational modeling efforts and advances in structural biology. We also provide similar details for 3 nuclear receptors known to regulate gene expression of these enzyme families.

Effect of UDP-glucuronosyltransferase 1A8 polymorphism on raloxifene glucuronidation

“…Although many in silico studies of human cytochrome P450s have been performed to predict inter-individual differences in xenobiotic metabolism and drug-drug interactio ns (Wang and Chou, 2010;DeLisle et al, 2011 ), few studies have focused on UGTs. In mammali an UGTs, only the X-ray crystal structure of the C-terminal domain of UGT2B7 has been reported (Miley et al, 2007 ), and the structural and functional data presented are thought to provide novel information and to have clarified numerous aspects of human UGT donor-substrate binding and catalytic activity.…”

Modeling of interactions between xenobiotics and cytochrome P450 (CYP) enzymes

“…Data on ADMET properties of compounds are increasingly generated using in vitro and in silico tools. Recent advances in molecular modeling of CYPs and other critical proteins demonstrate that it is possible to generate realistic models for them (DeLisle et al, 2011; Pelkonen et al, 2011; Carosati, 2013; Bessems et al, 2014). …”

Threonine-290 Regulates Nuclear Translocation of the Human Pregnane X Receptor through Its Phosphorylation/Dephosphorylation by Ca2+/Calmodulin-Dependent Protein Kinase II and Protein Phosphatase 1

“…PXR is a key transcriptional regulator of CYP3A, and CYP3A4 is known to catalyze the oxidative metabolism of most administered drugs (Lehmann et al, 1998;DeLisle et al, 2011). UGT1A1, plays a critical role in the detoxification of potentially neurotoxic bilirubin by conjugating it with glucuronic acid for excretion in bile (Ostrow and Murphy, 1970) and also conjugates drugs and other xenobiotics (Radominska-Pandya et al, 1999;Tukey and Strassburg, 2000).…”