MetaSite: Understanding metabolism in human cytochromes from the perspective of the chemist
MetaSite: Understanding metabolism in human cytochromes from the perspective of the chemist
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DOI：
10.1021/jm050529c
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发表时间：
2005-11-03
影响因子：
7.3
通讯作者：
Vianello, R
中科院分区：
文献类型：
--
作者：
Cruciani, G;Carosati, E;Vianello, R
代谢生物转化的鉴定可以显著影响药物发现过程。由于生物利用度、活性、毒性、分布和最终消除都取决于代谢生物转化，因此如果能够在发现阶段早期产生这些信息，将是非常有利的。一旦获得，这些信息可以帮助化学家判断是否应该从管道中删除潜在的候选物或对其进行修改以提高新化合物的化学稳定性或安全性。使用计算机模拟方法预测I期细胞色素介导的反应中的代谢位点是任何代谢途径预测的起点。本文提出了一种新的方法，专门为化学家设计的，提供了细胞色素参与和代谢的网站，任何人类细胞色素P450（CYP 1A 1）介导的反应作用于新的底物。该方法可以自动应用于所有已知3D结构的细胞色素，并且化学家可以使用该方法来检测应该保护的位置，以避免代谢降解或检查新支架或前药的适用性。全自动程序也是早期ADME-Tox测定（吸收、分布、代谢和排泄毒性测定）中的一种有价值的新工具，其中必须尽快和尽可能早地评估药物安全性和代谢特征模式。
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.