MetaSite:  Understanding Metabolism in Human Cytochromes from the Perspective of the Chemist

Cruciani, Gabriele; Carosati, Emanuele; Boeck, B. De; Ethirajulu, Kantharaj; Mackie, Claire; Howe, Trevor; Vianello, Riccardo

doi:10.1021/jm050529c

Cited by 453 publications

(391 citation statements)

References 39 publications

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“…Structures of drug-metabolizing P450s can be used to improve predictions of sites of metabolism and provide information for drug redesign to overcome metabolic barriers to improve efficacy or to reduce the likelihood of drug-drug interactions (62)(63)(64)(65). Hepatic clearance of drugs by P450-mediated metabolism is the most prevalent pathway for elimination of the 200 most prescribed drugs and is attributed in order of frequency to microsomal P450s 3A4, 2C9, 2D6, 2C19, 1A2, 2C8, and 2B6 (66).…”

Section: Drug-metabolizing Enzymesmentioning

confidence: 99%

Structural Diversity of Eukaryotic Membrane Cytochrome P450s

Johnson¹,

Stout

2013

Journal of Biological Chemistry

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X-ray crystal structures are available for 29 eukaryotic microsomal, chloroplast, or mitochondrial cytochrome P450s, including two non-monooxygenase P450s. These structures provide a basis for understanding structure-function relations that underlie their distinct catalytic activities. Moreover, structural plasticity has been characterized for individual P450s that aids in understanding substrate binding in P450s that mediate drug clearance.

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Section: Drug-metabolizing Enzymesmentioning

confidence: 99%

Structural Diversity of Eukaryotic Membrane Cytochrome P450s

Johnson¹,

Stout

2013

Journal of Biological Chemistry

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“…29 To produce more metabolically stable inhibitors, we first hypothesized that metabolism on the benzylic position is the most susceptible in these inhibitor skeletons. 30 We thus decided to take two approaches to improve the metabolic stability of the inhibitors: introduction of steric shields and removal of the metabolically susceptible position. Therefore, compounds were synthesized by introducing a methyl group or halogen atom(s) as steric shields on ortho position(s) of the phenyl ring, such as 3c-g and 9c-g, and by eliminating a methylene unit, such as 13a-g and 16a-g.…”

Section: Comparison Of Cis and Trans Isomersmentioning

confidence: 99%

Orally Bioavailable Potent Soluble Epoxide Hydrolase Inhibitors

Hwang

Tsai²,

Liu³

et al. 2007

J. Med. Chem.

215

262

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A series of N,N′-disubstituted ureas having a conformationally restricted cis-or trans-1,4-cyclohexane α to the urea were prepared and tested as soluble epoxide hydrolase (sEH) inhibitors. This series of compounds showed low nanomolar to picomolar activities against recombinant human sEH. Both isomers showed similar potencies, but the trans isomers were more metabolically stable in human hepatic microsomes. Furthermore, these new potent inhibitors show a greater metabolic stability in vivo than previously described sEH inhibitors. We demonstrated that trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid 13g (t-AUCB, IC 50 = 1.3 ± 0.05 nM) had excellent oral bioavailability (98%, n = 2) and blood area under the curve in dogs and was effective in vivo to treat hypotension in lipopolysaccharide challenged murine models.

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“…They are fast, but in most cases they predict a large number of possible metabolites despite the fact that in most cases only a few are formed experimentally. Important techniques are available that combine data from docking orientation and functional group reactivity for the prediction of metabolism, with good success in many cases (18).…”

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confidence: 99%

Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

Oláh

Mulholland

Harvey

2011

Proc. Natl. Acad. Sci. U.S.A.

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Cytochrome P450 enzymes play key roles in the metabolism of the majority of drugs. Improved models for prediction of likely metabolites will contribute to drug development. In this work, two possible metabolic routes (aromatic carbon oxidation and O-demethylation) of dextromethorphan are compared using molecular dynamics (MD) simulations and density functional theory (DFT). The DFT results on a small active site model suggest that both reactions might occur competitively. Docking and MD studies of dextromethorphan in the active site of P450 2D6 show that the dextromethorphan is located close to heme oxygen in a geometry apparently consistent with competitive metabolism. In contrast, calculations of the reaction path in a large protein model [using a hybrid quantum mechanical-molecular mechanics (QM/MM) method] show a very strong preference for O-demethylation, in accordance with experimental results. The aromatic carbon oxidation reaction is predicted to have a high activation energy, due to the active site preventing formation of a favorable transition-state structure. Hence, the QM/MM calculations demonstrate a crucial role of many active site residues in determining reactivity of dextromethorphan in P450 2D6. Beyond substrate binding orientation and reactivity of Compound I, successful metabolite predictions must take into account the detailed mechanism of oxidation in the protein. These results demonstrate the potential of QM/MM methods to investigate specificity in drug metabolism.C ytochrome P450 enzymes (P450s) form one of the most powerful defense mechanisms of living organisms: They protect against xenobiotics via an oxidative pathway, which in most instances leads to a less harmful and more soluble product with faster excretion. The same mechanism is involved in the metabolism of most drugs and alters the pharmacological activity of many drugs. As a consequence, P450-mediated transformations of drug candidates are of crucial importance in the pharmaceutical industry. The roles of P450s are manifold. Oxidation by P450s can lead to toxic products, but, on the other hand, local activation of, e.g., anticancer prodrugs by P450s to lethal intracellular toxins at the site of the tumor is an important strategy (1). Drug compounds can induce P450 expression but can also inhibit them in various ways (2-4). The metabolic clearance of most drugs depends on P450s, and they have been implicated in a large number of drug-drug interactions (5, 6), which can result in fatalities (7,8). Interactions of drug candidates with P450s must be taken into account during the drug discovery process if the expensive and time-consuming development of active compounds with hidden toxic effects is to be avoided.It is increasingly recognized that methods capable of predicting P450 oxidative activity for a given substrate, and also the predominant site(s) of metabolism, could contribute significantly to drug development. There are many aspects to this problem, including isoform selectivity (i.e., which P450 isoform will contribute mos...

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MetaSite: Understanding Metabolism in Human Cytochromes from the Perspective of the Chemist

Cited by 453 publications

References 39 publications

Structural Diversity of Eukaryotic Membrane Cytochrome P450s

Structural Diversity of Eukaryotic Membrane Cytochrome P450s

Orally Bioavailable Potent Soluble Epoxide Hydrolase Inhibitors

Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

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