Capture hydrolysis signals in the microsomal stability assay: Molecular mechanisms of the alkyl ester drug and prodrug metabolism
Capture hydrolysis signals in the microsomal stability assay: Molecular mechanisms of the alkyl ester drug and prodrug metabolism
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DOI：
10.1016/j.bmcl.2011.12.005
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发表时间：
2012-01-15
影响因子：
2.7
通讯作者：
Sun, Hao
中科院分区：
文献类型：
--
作者：
Sun, Hao
人肝微体中的羧酸酯酶经常催化羧酸酯的水解，这也是微体稳定性分析中常见的噪声，微体稳定性分析是药物开发中广泛使用的一种筛选方法，用于监测细胞色素P450酶的活性。在这里，我们通过对辉瑞公司的微粒体廓清数据库进行独特的成对分析，捕捉到了这种“噪音”，即小分子烷基酯类药物和前体药物的水解信号。用密度泛函理论和分子对接方法进一步阐明了水解物的作用机理。结果表明，酯基的电子性质、四面体的中间生成能和特定的药物-酶分子相互作用是决定所研究的烷基酯的代谢命运的关键因素，但单独而言，这些因素与观察到的水解率没有关联。(C)2011爱思唯尔有限公司。保留所有权利。
The hydrolysis of carboxylic acid esters is often catalyzed by carboxylesterases in human liver microsomes, which is also a common 'noise' in the microsomal stability assay, a widely used screening protocol in drug discovery to monitor the activity of cytochrome P450 enzymes. Herein, we captured this 'noise', the hydrolysis signal of small alkyl ester drugs and prodrugs with a unique pairwise analysis of Pfizer's microsomal clearance database. The hydrolysis mechanisms were further elucidated with density functional theory and molecular docking approaches. The results suggested that the electronic properties of ester moieties, tetrahedral intermediate formation energies, and specific drug-enzyme molecular interactions are key factors for the determination of the metabolic fate of the studied alkyl esters, but individually these factors failed to correlate with the observed rate of hydrolysis. (C) 2011 Elsevier Ltd. All rights reserved.