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MetaSite: Understanding Metabolism in Human Cytochromes from the Perspective of the Chemist
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Section:Abstract
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.
Citing Articles
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This article has been cited by 36 ACS Journal articles (5 most recent appear below).
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RS-Predictor: A New Tool for Predicting Sites of Cytochrome P450-Mediated Metabolism Applied to CYP 3A4
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Jed Zaretzki, Charles Bergeron, Patrik Rydberg, Tao-wei Huang, Kristin P. Bennett, and Curt M. BrenemanJournal of Chemical Information and Modeling2011 51 (7), 1667-1689This article describes RegioSelectivity-Predictor (RS-Predictor), a new in silico method for generating predictive models of P450-mediated metabolism for drug-like compounds. Within this method, potential sites of metabolism (SOMs) are represented as “...
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- Published In Issue November 03, 2005
- Received June 6, 2005
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