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Cited by 289

The DOI matches its Crossref record; 210 of the 210 references it cites were found in a registry or an index.

Computational Prediction of Metabolism: Sites, Products, SAR, P450 Enzyme Dynamics, and Mechanisms

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Kirchmair, Johannes, Williamson, Mark J., Tyzack, Jonathan D., Tan, Lu, Bond, Peter J., Bender, Andreas, Glen, Robert C.·2012·Journal of Chemical Information and Modeling
DOI 10.1021/ci200542m
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Abstract

Metabolism of xenobiotics remains a central challenge for the discovery and development of drugs, cosmetics, nutritional supplements, and agrochemicals. Metabolic transformations are frequently related to the incidence of toxic effects that may result from the emergence of reactive species, the systemic accumulation of metabolites, or by induction of metabolic pathways. Experimental investigation of the metabolism of small organic molecules is particularly resource demanding; hence, computational methods are of considerable interest to complement experimental approaches. This review provides a broad overview of structure- and ligand-based computational methods for the prediction of xenobiotic metabolism. Current computational approaches to address xenobiotic metabolism are discussed from three major perspectives: (i) prediction of sites of metabolism (SOMs), (ii) elucidation of potential metabolites and their chemical structures, and (iii) prediction of direct and indirect effects of xenobiotics on metabolizing enzymes, where the focus is on the cytochrome P450 (CYP) superfamily of enzymes, the cardinal xenobiotics metabolizing enzymes. For each of these domains, a variety of approaches and their applications are systematically reviewed, including expert systems, data mining approaches, quantitative structure-activity relationships (QSARs), and machine learning-based methods, pharmacophore-based algorithms, shape-focused techniques, molecular interaction fields (MIFs), reactivity-focused techniques, protein-ligand docking, molecular dynamics (MD) simulations, and combinations of methods. Predictive metabolism is a developing area, and there is still enormous potential for improvement. However, it is clear that the combination of rapidly increasing amounts of available ligand- and structure-related experimental data (in particular, quantitative data) with novel and diverse simulation and modeling approaches is accelerating the development of effective tools for prediction of in vivo metabolism, which is reflected by the diverse and comprehensive data sources and methods for metabolism prediction reviewed here. This review attempts to survey the range and scope of computational methods applied to metabolism prediction and also to compare and contrast their applicability and performance.

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Metadata

Authors
Kirchmair, J., Williamson, M. J., Tyzack, J. D., Tan, L., Bond, P. J., Bender, A., & Glen, R. C.
Venue
Journal of Chemical Information and Modeling
Publisher
American Chemical Society (ACS)
Published
2012-02-17
Volume
52
Issue
3
Pages
617-648
ISSN
  • 1549-9596 (ISSN-L)
  • 1549-960X
DOI
10.1021/ci200542m
OpenAlex
W2090505208
Cited by
289
References
210
FWCI
36.99
Type
journal article
Language
en
Open access
hybrid

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