State-of-the-art tools for computational site of metabolism predictions: Comparative analysis, mechanistical insights, and future applications

被引:93
作者
Afzelius, Lovisa [1 ]
Arnby, Catrin Hasselgren
Broo, Anders
Carlsson, Lars
Isaksson, Christine
Jurva, Ulrik
Kjellander, Britta
Kolmodin, Karin
Nilsson, Kristina
Raubacher, Florian
Weidolf, Lars
机构
[1] AstraZeneca R&D, DMPK&Bioanalyt Chem, S-43183 Molndal, Sweden
[2] AstraZeneca R&D, Lead Generat, S-43183 Molndal, Sweden
[3] AstraZeneca R&D, Safety Assessement, S-43183 Molndal, Sweden
[4] AstraZeneca R&D, Discovery Enabling Capabil & Sci, S-43183 Molndal, Sweden
关键词
cytochrome P450 (CYP450); metabolism; heme; computational prediction; structure-based design; ligand-based design; reactivity; DFT; docking; data mining;
D O I
10.1080/03602530600969374
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:61 / 86
页数:26
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