Structure-Based Site of Metabolism Prediction for Cytochrome P450 2D6

Moors, Samuel L. C.; Vos, Ann; Cummings, Maxwell D.; Vlijmen, Herman van; Ceulemans, Arnout

doi:10.1021/jm2006468

Cited by 45 publications

(55 citation statements)

References 44 publications

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“…Therefore, most prediction systems reported previously, such as ligand structure-based pharmacophore models and enzyme structure-based homology models, are applicable to certain categories of chemical ligands but not to all substrates of CYP2D6 (Moors et al, 2011). The present system has shown applicability to a wide variety of chemicals as a unified system.…”

Section: Discussionmentioning

confidence: 97%

Unimolecular and Bimolecular Binding System for the Prediction of CYP2D6-Mediated Metabolism

Sato¹,

Yamazoe²

2011

Drug Metab Dispos

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ABSTRACT:We have developed a template system for the prediction of CYP2D6-mediated metabolism of compounds. The system is composed of two types of two-dimensional templates (templates A and B), which were generated from mutually occupied areas of typical CYP2D6 substrates. The areas of templates are expressed as hexagonal blocks for application to the two-dimensional structures of chemicals. Experiments with 93 reactions with 69 typical substrates indicated the necessity for two similar but distinct shapes for template A (A1 and A2) for optimal placement. A frequently occupied area for substrates in template A1 was defined as a trigger area in which to capture a substrate for initiation of metabolism. Another frequently occupied area was found near the site of metabolism in template B. Both frequently occupied areas are linked to a pinching area. Occupancy of substrates on two template areas is suggested to be essential for the metabolism of CYPD6 substrates. In cases of CYP2D6 substrates without simultaneous occupancy of both areas, bimolecular placement, in which two molecules are placed coordinately, is proposed. Metabolism of small molecules, including naphthalene and quinoline, became explainable with the use of this idea. Validation of this template system with the use of both good and poor CYP2D6 substrates indicated clear advantages of the present system as a tool for drug modification, in addition to enabling highly accurate estimation of the site of metabolism.

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Section: Discussionmentioning

confidence: 97%

Unimolecular and Bimolecular Binding System for the Prediction of CYP2D6-Mediated Metabolism

Sato¹,

Yamazoe²

2011

Drug Metab Dispos

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“…The prediction accuracy for both the training and the test sets are shown in Table 2 and show that the SMARTCyp 2D6 model gives higher accuracy as compared to both the dockingbased model of Moors et al 12 and the ligand-based model in the StarDrop software, 13 especially with regard to finding a SOM in the top-ranked position.…”

Section: * S Supporting Informationmentioning

confidence: 97%

“…However, because the binding plays such a large role, it is necessary to include implicitly this information in the ligandbased models to predict the SOMs. Here, we present a variant of the SMARTCyp method that, in addition to the intrinsic reactivity and accessibility, takes the presence of a positive charge in the compound into account and shows that this gives a model able to accurately predict CYP 2D6 metabolism.The data sets from Moors et al 12 were, with some modifications, used to build and validate the SMARTCYPbased 2D6 models. Because we are building models based on 2D structures, first, we removed one of each duplicate R and S isomers.…”

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confidence: 99%

Ligand-Based Site of Metabolism Prediction for Cytochrome P450 2D6

Rydberg

Olsen

2011

ACS Med. Chem. Lett.

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A ligand-based method based on the SMARTCyp approach that predicts the sites of cytochrome P450 2D6-mediated metabolism of druglike molecules has been developed. The method uses only two descriptors besides the reactivity from SMARTCyp: the distance to a protonated nitrogen atom and the distance to the end of the molecule. Hence, the site of metabolism is predicted directly from the 2D structure of a molecule, without requiring calculation of electronic properties or generation of 3D structures. Testing on an independent test set gives an area under the curve value of 0.94, and a site of metabolism is found among the top two ranked atoms for 91% of the compounds. KEYWORDS: CYP2D6, cytochrome P450, drug metabolism C ytochrome P450 (CYP) constitutes an ubiquitous family of enzymes, and from a drug perspective, its most important function is to metabolize drug compounds. In the development of drugs, it is important at an early stage to be able to identify the site of metabolism (SOM) of the lead compounds to be able to guide the development of compounds with a desirable pharmacokinetic profile.The CYP 3A4 isoform is the most important enzyme in the degradation of drug compounds and metabolize about 50% of them. CYP 3A4 is promiscuous and is capable of converting both small and large compounds, and crystal structures have shown that the volume of the active site can change dramatically upon binding of ligands. 1−3 This is probably also why it is possible to use ligand-based models to predict how a druglike compound is metabolized for CYP 3A4, because binding in this flexible pocket is not too restrictive, and thus, the intrinsic reactivity plays a significant role. For example, it was possible with the SMARTCyp method, 4,5 which primarily takes the intrinsic reactivity into account, to predict a SOM within the top two ranked atoms for 81% of the compounds within a set of 361 druglike compounds. 5 The second most drug-metabolizing CYP enzyme, the 2D6 isoform, is more selective in its recognition of the substrates. Generally, many medium-sized amines are metabolized, however, not many of them by N-dealkylation of amines but rather further away from this functional group. The crystal structure of CYP 2D6 reveals that a there are two negatively charged amino acids in the upper part of the binding cavity of 2D6, that is, Glu216 and Asp301, which may facilitate the binding of the positively charged parts of the substrates. 6 The fact that the enzyme induces the binding suggests that it is relevant to use the protein structures to predict how drug compounds are metabolized. This is probably why only few studies of pure ligand-based models on SOM prediction for CYP2D6 exist, 7 and structural information of protein has been included for these purposes. de Groot and co-workers combined structural models of CYP2D6 and pharmacophore modeling with AM1 energies of intermediates and products to predict the SOMs. 8,9 Later studies have shown the importance of including water molecules and using ensembles of protein struct...

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“…The concept of ensemble docking has since then been applied more often to CYP enzymes, in particular for the bacterial CYP102A1 (CYP BM3) [49] and for the human isoforms 2D6 [50] and 3A4 [51]. In the latter study, 16 substrates were docked into 125 protein structures as obtained from MD simulations.…”

Section: Protein Flexibilitymentioning

confidence: 99%

Structure‐Based Methods for Predicting the Sites and Products of Metabolism

Oostenbrink

2014

Methods and Principles in Medicinal Chemistry

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IntroductionCytochrome P450s (CYPs) are heme-containing enzymes that can be found in virtually all organisms. In humans, the CYP superfamily constitutes the most important enzymes in drug metabolism (see Chapters 4-8).Various computational approaches to study CYP metabolism have been reported over the years [1][2][3][4], and depending on the question that is being addressed, different methods may be more or less appropriate. For instance, if the actual reaction mechanism of a particular substrate is to be studied, a quantum mechanical description explicitly describing the electrons that are responsible for bonds being broken and formed is required [5]. On the other hand, a classification of a large number of compounds in terms of their likelihood to show an interaction with a CYP may rather be performed by application of cheminformatics machine learning tools [6]. In almost all cases, the versatility of the enzymes, the diversity of the substrates and inhibitors, and the malleability of the active sites pose additional challenges to the computational approach at hand. This chapter focuses on structure-based approaches to study the metabolism of substrates by CYP enzymes. Rather than addressing the actual enzymatic reactions, as in Chapters 6 and 11, we will focus here on the preferred orientations of substrates in the active site of CYP enzymes as a crucial first step in the prediction of metabolism. Using mostly examples from our own work, we will highlight some of the possibilities and challenges in structure-based predictions of sites of metabolism (SoMs). 6 Å RuleThe basic concept behind structure-based prediction of metabolism by CYP enzymes is extremely simple. The crucial cofactor of the enzymes is a heme 243 Drug Metabolism Prediction, First Edition. Edited by Johannes Kirchmair.

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Structure-Based Site of Metabolism Prediction for Cytochrome P450 2D6

Cited by 45 publications

References 44 publications

Unimolecular and Bimolecular Binding System for the Prediction of CYP2D6-Mediated Metabolism

Unimolecular and Bimolecular Binding System for the Prediction of CYP2D6-Mediated Metabolism

Ligand-Based Site of Metabolism Prediction for Cytochrome P450 2D6

Structure‐Based Methods for Predicting the Sites and Products of Metabolism

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