MetaSite: Understanding metabolism in human cytochromes from the perspective of the chemist

被引:380
作者
Cruciani, G
Carosati, E
De Boeck, B
Ethirajulu, K
Mackie, C
Howe, T
Vianello, R
机构
[1] Univ Perugia, Dept Chem, Lab Chemometr & Cheminformat, I-06123 Perugia, Italy
[2] Johnson & Johnson Pharmaceut Res & Dev, Dept Med Chem, B-2340 Beerse, Belgium
[3] Johnson & Johnson Pharmaceut Res & Dev, Dept ADME, B-2340 Beerse, Belgium
[4] Johnson & Johnson Pharmaceut Res & Dev, Dept Mol Informat, B-2340 Beerse, Belgium
[5] Mol Discovery Ltd, Pinner HA5 5NE, Middx, England
关键词
D O I
10.1021/jm050529c
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:6970 / 6979
页数:10
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