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

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Laboratory for Chemometrics and Cheminformatics, Department of Chemistry, University of Perugia, Via Elce di Sotto, 10, I-06123, Perugia, Italy, Departments of Medicinal Chemistry, ADME, and Molecular Informatics, Johnson and Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse, Belgium, and Molecular Discovery Ltd., 215 Marsh Road, Pinner, Middlesex, HA5 5NE London, U.K.
Cite this: J. Med. Chem. 2005, 48, 22, 6970–6979
Publication Date (Web):September 30, 2005
Copyright © 2005 American Chemical Society

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    Identification of metabolic biotransformations can significantly affect the drug discovery process. Since bioavailability, activity, toxicity, distribution, and final elimination all depend on metabolic biotransformations, it would be extremely advantageous if this information could be produced early in the discovery phase. Once obtained, this information can help chemists to judge whether a potential candidate should be eliminated from the pipeline or modified to improve chemical stability or safety of new compounds. The use of in silico methods to predict the site of metabolism in phase I cytochrome-mediated reactions is a starting point in any metabolic pathway prediction. This paper presents a new method, specifically designed for chemists, that provides the cytochrome involved and the site of metabolism for any human cytochrome P450 (CYP) mediated reaction acting on new substrates. The methodology can be applied automatically to all the cytochromes for which 3D structure is known and can be used by chemists to detect positions that should be protected in order to avoid metabolic degradation or to check the suitability of a new scaffold or prodrug. The fully automated procedure is also a valuable new tool in early ADME-Tox assays (absorption, distribution, metabolism, and excretion toxicity assays), where drug safety and metabolic profile patterns must be evaluated as soon, and as early, as possible.

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     To whom correspondence should be addressed. Phone:  +39-075-5855550. Fax:  +39-075-45646. E-mail:  [email protected].

     University of Perugia.

     Department of Medicinal Chemistry, Johnson and Johnson Pharmaceutical Research and Development.


     Department of ADME, Johnson and Johnson Pharmaceutical Research and Development.


     Department of Molecular Informatics, Johnson and Johnson Pharmaceutical Research and Development.

     Molecular Discovery Ltd.

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    Structures of compounds presented in all the examples in the SMILES format and additional details on the calculations of Ei and Ri components and substrate selectivity model. This material is available free of charge via the Internet at

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