State-of-the-art Tools for Computational Site of Metabolism Predictions: Comparative Analysis, Mechanistical Insights, and Future Applications

• Published in: Drug metabolism reviews 2007, Vol.39 (1), p.61-86
• Main Authors: Afzelius, Lovisa, Hasselgren Arnby, Catrin, Broo, Anders, Carlsson, Lars, Isaksson, Christine, Jurva, Ulrik, Kjellander, Britta, Kolmodin, Karin, Nilsson, Kristina, Raubacher, Florian, Weidolf, Lars
• Format: Article
• Language: English
• Subjects: Algorithms; Aryl Hydrocarbon Hydroxylases - metabolism; Binding Sites; Biological and medical sciences; Computational Biology - methods; Computational Biology - trends; Computational prediction; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450 (CYP450); Data mining; DFT; Docking; Heme; Humans; Hydrophobic and Hydrophilic Interactions; Ligand-based design; Medical sciences; Metabolism; Molecular Structure; Pharmaceutical Preparations - chemistry; Pharmaceutical Preparations - metabolism; Pharmacology. Drug treatments; Principal Component Analysis; Reactivity; Structure-based design
• ISSN: 0360-2532; 1097-9883
• DOI: 10.1080/03602530600969374

In drug design, it is crucial to have reliable information on how a chemical entity behaves in the presence of metabolizing enzymes. This requires substantial experimental efforts. Consequently, being able to predict the likely site s of metabolism in any compound, synthesized or virtual, would be highly beneficial and time efficient. In this work, six different methodologies for predictions of the site of metabolism (SOM) have been compared and validated using structurally diverse data sets of drug-like molecules with well-established metabolic pattern in CYP3A4, CYP2C9, or both. Three of the methods predict the SOM based on the ligand's chemical structure, two additional methods use structural information of the enzymes, and the sixth method combines structure and ligand similarity and reactivity. The SOM is correctly predicted in 50 to 90% of the cases, depending on method and enzyme, which is an encouraging rate. We also discuss the underlying mechanisms of cytochrome P450 metabolism in the light of the results from this comparison.