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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. [ABSTRACT FROM AUTHOR]

Ion mobility-mass spectrometry (IM-MS) has gained increased applications in the characterization and identification of drugs and drug metabolites, largely owning to the complementary separation of analyte ions based on their gas-phase size and shape in the IM dimension in addition to their mass-to-charge ratios. In this review, we discuss recent advances in such applications. We first introduce various types of IM techniques, focusing on those that allow the measurement of collision cross section (CCS), the physical property of an ion that reflects its gas-phase size and shape. Next, we discuss the IM-MS landscape of the large chemical space of drugs and multimodal distributions of certain drugs in IM separation due to the presence of protomers. We then review drug metabolism reactions and discuss the application of IM-MS in separation and identification of isomeric drug metabolites. Subsequently, we discuss various approaches to generate theoretical and predicted CCS data, including theory-based calculation methods and data-driven prediction models, and currently available resources on these approaches. Finally, current limitations and future directions of application of IM-MS are discussed. [Display omitted] • IM-MS landscape of the large chemical space of drugs. • Multimodal distribution of protomers of drugs in IM separation. • Characterization and identification of isomeric drug metabolites. • Theoretical approaches for the calculation and prediction of collision cross sections. [ABSTRACT FROM AUTHOR]