State-of-the-art Tools for Computational Site of Metabolism Predictions: Comparative Analysis, Mechanistical Insights, and Future Applications

Afzelius, Lovisa; Arnby, Catrin Hasselgren; Broo, Anders; Carlsson, Lars; Isaksson, Christine; Jurva, Ulrik; Kjellander, B. K. Charlotte; Kolmodin, Karin; Nilsson, K. Peter R.; Raubacher, Florian; Weidolf, Lars

doi:10.1080/03602530600969374

Cited by 118 publications

(117 citation statements)

References 38 publications

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“…The degree of success is likely to vary depending on the compound series of interest. Nevertheless, recent work within AstraZeneca demonstrates that the protein conformation seen in the ketoconazole structure performed well in structure-based site-of-metabolism predictions for many CYP3A4 substrates (24).…”

Section: Resultsmentioning

confidence: 99%

Structural basis for ligand promiscuity in cytochrome P450 3A4

Ekroos

Sjögren

2006

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

684

722

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Cytochrome P450 (CYP) 3A4 is the most promiscuous of the human CYP enzymes and contributes to the metabolism of Ϸ50% of marketed drugs. It is also the isoform most often involved in unwanted drug-drug interactions. A better understanding of the molecular mechanisms governing CYP3A4 -ligand interaction therefore would be of great importance to any drug discovery effort. Here, we present crystal structures of human CYP3A4 in complex with two well characterized drugs: ketoconazole and erythromycin. In contrast to previous reports, the protein undergoes dramatic conformational changes upon ligand binding with an increase in the active site volume by >80%. The structures represent two distinct open conformations of CYP3A4 because ketoconazole and erythromycin induce different types of coordinate shifts. The binding of two molecules of ketoconazole to the CYP3A4 active site and the clear indication of multiple binding modes for erythromycin has implications for the interpretation of the atypical kinetic data often displayed by CYP3A4. The extreme flexibility revealed by the present structures also challenges any attempt to apply computational design tools without the support of relevant experimental data.drug metabolism ͉ structural flexibility ͉ x-ray crystallography ͉ inhibitor ͉ substrate C ytochrome P450 3A4 (CYP3A4) is the most abundant of the xenobiotic-metabolizing CYP isoforms, and interactions with CYP3A4 must always be taken into consideration during the development of new medications (1).In recent years, a number of structures of mammalian CYP isoforms, including CYP2C5 (2), CYP2C9 (3, 4), CYP2C8 (5), CYP2B4 (6), CYP2A6 (7), and CYP3A4 (8, 9) have been solved. All of these structures were determined from modified versions of the protein where the N-terminal transmembrane helix was truncated and, in some cases, a number of mutations aimed at increasing solubility were introduced. The mammalian CYP structures all adopt the general CYP fold first described in 1987 when the structure of the bacterial P450 CYP101 was determined by x-ray crystallography (10).The ligand-free structure of CYP3A4 was published in 2004 by two independent groups (8, 9). These structures are very similar (11). The most remarkable features are the short F and G helices (nomenclature adapted from Poulos et al.; ref. 10) and a large, highly ordered hydrophobic core of phenyl alanine residues above the active site (8, 9). CYP3A4 is known to metabolize large substrates such as bromocriptine (M r 655 Da) and cyclosporine (M r 1,203 Da). A number of studies also indicate that CYP3A4 displays ligand binding that does not follow Michaelis-Menten type kinetics, and it has been suggested that two or more ligand molecules can bind to the CYP3A4 active site simultaneously (12-15). In light of these observations, the volume of the active site in the published ligand-free structures is smaller than expected, comparable with the active-site cavity seen in CYP2C9 and CYP2C8, which led Williams et al. (8) to speculate that conformational changes may o...

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Section: Resultsmentioning

confidence: 99%

Structural basis for ligand promiscuity in cytochrome P450 3A4

Ekroos

Sjögren

2006

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

684

722

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“…To perform structurebased drug metabolism prediction, experimentally determined (such as use of X-ray crystallography) structures of drug-metabolizing enzymes are required. In the absence of the crystal structures, homology models of the enzymes can be used to evaluate the binding modes and predict interactions of the functional groups in the molecule with the key amino acid residues (de Groot, 2006;Afzelius et al, 2007;Sun and Scott, 2010). Because the crystal structure of human AO was not available, the three-dimensional homology model of human AO, which was constructed using the crystal structure of bovine xanthine dehydrogenase (XDH) as a template and guided by multiple alignments using bovine, rabbit, and rat sequences of AO as well as the sequence of chicken XDH, was used.…”

Section: Molecular Modeling Studiesmentioning

confidence: 99%

Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide

Dalvie

Sun²,

Xiang³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Current studies explored the effect of structural changes on the aldehyde oxidase (AO)-mediated metabolism of zoniporide (1). Zoniporide analogs with modifications of the acylguanidine moiety, the cyclopropyl group on the pyrazole ring, and the quinoline ring were studied for their AO-catalyzed metabolism using the human S9 fraction. Analysis of the half-lives suggested that subtle changes in the structure of 1 influenced its metabolism and that the guanidine and the quinoline moieties were prerequisites for AO-catalyzed oxidation to 2-oxozoniporide (M1). In contrast, replacement of the cyclopropyl group with other alkyl groups was tolerated. The effect of structural variation on AO properties was rationalized by docking 1 and its analogs into the human AO homology model. These studies indicated the importance of electrostatic, -stacking and hydrophobic interactions of the three motifs with residues in the active site. Differences in substrate properties were also rationalized by comparing their half-lives with cLogD, electrophilicity parameters [electrostatic potential (ESP) charges and energy of lowest unoccupied molecular orbitals (E LUMO )], and the energies of formation of tetrahedral intermediates (J Med Chem 50:4642-4647, 2007). Whereas the success of energetics in predicting the AO substrate properties of analogs was 87%, the predictive ability of other descriptors was none (cLogD) to 60% (ESP charges and E LUMO ). Overall, the structuremetabolism relationship could be rationalized using a combination of both the energy calculations and docking studies. This combination method can be incorporated into a strategy for mitigating AO liabilities observed in the lead candidate or studying structuremetabolism relationships of other AO substrates.

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“…For CYP3A4 substrates, approximately half of the known metabolism reactions occur via hydroxylation, the rate limiting step of which is hydrogen atom abstraction (Sheridan et al, 2007). Knowing where a molecule is preferentially oxidized by this cytochrome would aid the modification of compounds to improve their kinetic or pharmacological profiles (Afzelius et al, 2007).…”

Section: Motivating Applicationmentioning

confidence: 99%

Multiple instance ranking

Bergeron

Zaretzki

Breneman

et al. 2008

Proceedings of the 25th International Conference on Machine Learning - ICML '08

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This paper introduces a novel machine learning model called multiple instance ranking (MIRank) that enables ranking to be performed in a multiple instance learning setting. The motivation for MIRank stems from the hydrogen abstraction problem in computational chemistry, that of predicting the group of hydrogen atoms from which a hydrogen is abstracted (removed) during metabolism. The model predicts the preferred hydrogen group within a molecule by ranking the groups, with the ambiguity of not knowing which hydrogen atom within the preferred group is actually abstracted. This paper formulates MIRank in its general context and proposes an algorithm for solving MIRank problems using successive linear programming. The method outperforms multiple instance classification models on several real and synthetic datasets.

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State-of-the-art Tools for Computational Site of Metabolism Predictions: Comparative Analysis, Mechanistical Insights, and Future Applications

Cited by 118 publications

References 38 publications

Structural basis for ligand promiscuity in cytochrome P450 3A4

Structural basis for ligand promiscuity in cytochrome P450 3A4

Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide

Multiple instance ranking

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