Large-Scale Structural Characterization of Drug and Drug-Like Compounds by High-Throughput Ion Mobility-Mass Spectrometry.
Large-Scale Structural Characterization of Drug and Drug-Like Compounds by High-Throughput Ion Mobility-Mass Spectrometry.
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DOI：
10.1021/acs.analchem.7b01709
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发表时间：
2017-09-05
影响因子：
7.4
通讯作者：
Xu L
中科院分区：
文献类型：
--
作者：
Hines KM;Ross DH;Davidson KL;Bush MF;Xu L
离子迁移-质谱（IM-MS）可以提供正交信息，即，m/z和碰撞截面（CCS），用于药物和药物代谢物的鉴定。然而，只有少量的CCS值可用于药物，这限制了使用CCS作为识别参数和使用IM-MS的药物的结构-功能关系的评估。在这里，我们报告了一个快速的工作流程的发展，用于测量CCS值的大量的药物或药物样分子在氮气中广泛使用的行波IM-MS（TWIM-MS）平台。使用小分子和多肽CCS校准品的组合，我们使用384孔板的流动注射分析成功地测定了MicroSource Discovery Systems光谱收集中1425种药物或药物样分子的氮CCS值。开发了软件以简化数据提取、处理和校准。我们发现，整体药物收集涵盖了广泛的CCS范围相同的质量，这表明这些药物的结构多样性很大。然而，个别药物类别似乎占据了一个狭窄的和独特的空间，在CCS质量二维光谱，这表明一个紧密的结构功能关系的每一类药物与特定的目标。我们观察到双峰分布的几个抗生素物种由于多个原异构体，包括已知的氟喹诺酮类原异构体和新发现的头孢菌素原异构体。最后，我们通过快速自信地确认药品中的活性成分，证明了高通量方法和药物CCS数据库的实用性。
Ion mobility-mass spectrometry (IM-MS) can provide orthogonal information, i.e., m/z and collision cross section (CCS), for the identification of drugs and drug metabolites. However, only a small number of CCS values are available for drugs, which limits the use of CCS as an identification parameter and the assessment of structure–function relationships of drugs using IM-MS. Here, we report the development of a rapid workflow for the measurement of CCS values of a large number of drug or drug-like molecules in nitrogen on the widely available traveling wave IM-MS (TWIM-MS) platform. Using a combination of small molecule and polypeptide CCS calibrants, we successfully determined the nitrogen CCS values of 1425 drug or drug-like molecules in the MicroSource Discovery Systems’ Spectrum Collection using flow injection analysis of 384-well plates. Software was developed to streamline data extraction, processing, and calibration. We found that the overall drug collection covers a wide CCS range for the same mass, suggesting a large structural diversity of these drugs. However, individual drug classes appear to occupy a narrow and unique space in the CCS–mass 2D spectrum, suggesting a tight structure–function relationship for each class of drugs with a specific target. We observed bimodal distributions for several antibiotic species due to multiple protomers, including the known fluoroquinolone protomers and the new finding of cephalosporin protomers. Lastly, we demonstrated the utility of the high-throughput method and drug CCS database by quickly and confidently confirming the active component in a pharmaceutical product.
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影响因子：
1.8
作者：
McLean, JA;Ruotolo, BT;Russell, DH
通讯作者：
Russell, DH
影响因子：
7.4
作者：
Paglia, Giuseppe;Angel, Peggi;Williams, Jonathan P.;Richardson, Keith;Olivos, Hernando J.;Thompson, J. Will;Menikarachchi, Lochana;Lai, Steven;Walsh, Callee;Moseley, Arthur;Plumb, Robert S.;Grant, David F.;Palsson, Bernhard O.;Langridge, James;Geromanos, Scott;Astarite, Giuseppe
通讯作者：
Astarite, Giuseppe
DOI：
10.1007/s13361-010-0037-0
发表时间：
2011-02-01
影响因子：
3.2
作者：
Joyce, J. Richard;Richards, Don S.
通讯作者：
Richards, Don S.
影响因子：
7.4
作者：
Campuzano, Iain;Bush, Matthew F.;Kim, Hugh I.
通讯作者：
Kim, Hugh I.
影响因子：
8.6
作者：
Hanwell MD;Curtis DE;Lonie DC;Vandermeersch T;Zurek E;Hutchison GR
通讯作者：
Hutchison GR