Structure, Design, Informatics, Sanofi-Aventis US, 1041 Rt 202/206N, Bridgewater, NJ 08807, USA.
Expert Opin Drug Metab Toxicol. 2010 Jul;6(7):851-61. doi: 10.1517/17425255.2010.499123.
The site of metabolism (SOM) predictions by CYP 3A4 are extremely important during the drug discovery process especially during the lead discovery or library design phases. With the ability to rapidly characterize metabolites from these enzymes, the challenges facing in silico contribution change during the drug optimization phase. Some of the challenges are addressed in this article. Some aspects of the SOM prediction software and methodology are discussed in this opinion article and examples of software utility in overcoming metabolic instability in drug optimization are shown.
SOM prediction by various approaches is discussed. Two ways of overcoming metabolic instability, blocking the metabolic softspots and rational modification of the instable molecule to avoid interaction with the CYP pocket, are discussed. The contribution plot in MetaSite and its use are discussed.
The reader will gain an understanding of possible approaches to either blocking the metabolic softspot or rationally modifying the molecule using MetaSite software or docking approaches. Blocking metabolism using fluorination has risks especially introducing multifluorinated benzene rings in the molecule.
During the lead optimization phase of drug discovery, when metabolic instability is an issue in a series, in silico approaches can be used to modify the molecule in order to decrease clearance due to metabolism, even that due to CYP3A4.
CYP 3A4 的代谢部位 (SOM) 预测在药物发现过程中非常重要，特别是在先导物发现或库设计阶段。通过快速表征这些酶的代谢物的能力，在药物优化阶段，计算贡献所面临的挑战发生了变化。本文解决了其中的一些挑战。本文讨论了 SOM 预测软件和方法的某些方面，并展示了软件在克服药物优化中代谢不稳定性方面的应用实例。
讨论了各种方法的 SOM 预测。讨论了克服代谢不稳定性的两种方法，即阻断代谢脆弱点和合理修饰不稳定分子以避免与 CYP 口袋相互作用。讨论了 MetaSite 中的贡献图及其用途。
读者将了解使用 MetaSite 软件或对接方法阻断代谢脆弱点或合理修饰分子的可能方法。使用氟化来阻止代谢存在风险，尤其是在分子中引入多氟化苯环。
在药物发现的先导优化阶段，如果一系列化合物存在代谢不稳定性问题，可以使用计算方法来修饰分子，以降低因代谢（包括 CYP3A4 引起的代谢）导致的清除率。
