MetaSite: Understanding Metabolism in Human Cytochromes from the Perspective of the Chemist
Top Cited Papers
- 30 September 2005
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 48 (22), 6970-6979
- https://doi.org/10.1021/jm050529c
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.Keywords
This publication has 19 references indexed in Scilit:
- Pharmacophore, Drug Metabolism, and Pharmacokinetics Models on Non-Peptide AT1, AT2, and AT1/AT2 Angiotensin II Receptor AntagonistsJournal of Medicinal Chemistry, 2005
- Hydrogen Bonding Interactions of Covalently Bonded Fluorine Atoms: From Crystallographic Data to a New Angular Function in the GRID Force FieldJournal of Medicinal Chemistry, 2004
- Open-access high-resolution mass spectrometry in early drug discoveryJournal of Mass Spectrometry, 2004
- Simultaneous measurement of drug metabolic stability and identification of metabolites using ion‐trap mass spectrometryRapid Communications in Mass Spectrometry, 2003
- LC–NMR–MS in drug discoveryDrug Discovery Today, 2003
- Liquid chromatography/atmospheric pressure ionization–mass spectrometry in drug metabolism studiesJournal of Mass Spectrometry, 2003
- Cytochrome P450 Substrate Specificities, Substrate Structural Templates and Enzyme Active Site GeometriesDrug Metabolism and Drug Interactions, 1999
- Metabolism of carteolol by cDNA-expressed human cytochrome P450European Journal of Clinical Pharmacology, 1997
- The Substrate Binding Site of Human Liver Cytochrome P450 2C9: An Approach Using Designed Tienilic Acid Derivatives and Molecular ModelingBiochemistry, 1995
- A computational procedure for determining energetically favorable binding sites on biologically important macromoleculesJournal of Medicinal Chemistry, 1985