Sites of metabolic substitution: investigating metabolite structures utilising ion mobility and molecular modelling
Sites of metabolic substitution: investigating metabolite structures utilising ion mobility and molecular modelling
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DOI：
10.1002/rcm.4742
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发表时间：
2010-11-01
影响因子：
2
通讯作者：
Campuzano, Iain
中科院分区：
文献类型：
--
作者：
Dear, Gordon J.;Munoz-Muriedas, Jordi;Campuzano, Iain
药物代谢是药物开发和药物发现过程中不可分割的一部分。需要验证代谢物的毒性，以支持安全性测试，特别是提供关于形成药理活性或毒性代谢物的可能性的信息。目前选择的代谢物结构解析方法是液相色谱/串联质谱（LC/MS/MS）和核磁共振（NMR）光谱。在某些情况下，代谢物的代谢位点不能仅通过MS/MS明确地确定。利用市售的分子动力学包和已知的量子化学基础集，生成了模型化合物昂丹司琼的一组芳香羟基化代谢物的最低能量结构集合。计算了各结构的理论碰撞截面。行波离子迁移率（IMS）测量也进行了化合物，从而使实验推导的碰撞截面计算。理论和实验推导的碰撞截面的比较被用于精确分配同分异构体药物代谢物。本文描述的UPLC/IMS-MS方法证明了通过离子迁移率、代谢物结构异构体（理论和实验推导的碰撞截面差异小于1埃）进行重复性测量的能力(2)。该应用具有补充和/或补充当前代谢物结构表征方法的潜力。版权所有John Wiley & Sons， Ltd。
Drug metabolism is an integral part of the drug development and drug discovery process. It is required to validate the toxicity of metabolites in support of safety testing and in particular provide information on the potential to form pharmacologically active or toxic metabolites. The current methodologies of choice for metabolite structural elucidation are liquid chromatography/tandem mass spectrometry (LC/MS/MS) and nuclear magnetic resonance (NMR) spectroscopy. There are, in certain cases, examples of metabolites whose sites of metabolism cannot be unequivocally identified by MS/MS alone. Utilising commercially available molecular dynamics packages and known quantum chemistry basis sets, an ensemble of lowest energy structures were generated for a group of aromatic hydroxylated metabolites of the model compound ondansetron. Theoretical collision cross sections were calculated for each structure. Travelling-wave ion mobility (IMS) measurements were also performed on the compounds, thus enabling experimentally derived collision cross-sections to be calculated. A comparison of the theoretical and experimentally derived collision cross-sections were utilised for the accurate assignment of isomeric drug metabolites. The UPLC/IMS-MS method, described herein, demonstrates the ability to measure reproducibly by ion mobility, metabolite structural isomers, which differ in collision cross-section, both theoretical and experimentally derived, by less than 1 angstrom(2). This application has the potential to supplement and/or complement current methods of metabolite structural characterisation. Copyright (C) 2010 John Wiley & Sons, Ltd.