Elucidation Of Drug Metabolite Structural Isomers Using Molecular Modeling Coupled With Ion Mobility Mass Spectrometry | 52839
Journal of Analytical & Bioanalytical Techniques
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Ion mobility-mass spectrometry (IM-MS) in combination with molecular modeling offers the potential for small molecule
structural isomer identification by measurement of their gas phase collision cross sections (CCSs). Successful application of
this approach to drug metabolite identification would facilitate resource reduction, including animal usage, and may benefit
other areas of pharmaceutical structural characterization including impurity profiling and degradation chemistry. However,
the conformational behavior of drug molecules and their metabolites in the gas phase is poorly understood. We investigated the
gas phase conformational space of drug and drug-like molecules as well as the influence of protonation and adduct formation
on the conformations of drug metabolite structural isomers. The use of CCSs, measured from IM-MS and molecular modeling
information, for the structural identification of drug metabolites has also been critically assessed. Detection of structural
isomers of drug metabolites using IM-MS is demonstrated and, in addition, a molecular modeling approach has been developed
offering rapid conformational searching and energy assessment of candidate structures which agree with experimental CCSs.
Here, it is illustrated that isomers must possess markedly dissimilar CCS values for structural differentiation, the existence
and extent of CCS differences being ionization state and molecule dependent. The results present that IM-MS and molecular
modeling can inform on the identity of drug metabolites and highlight the limitations of this approach in differentiating
Eamonn Reading has completed his PhD from the University of Oxford and completed a year’s Post-doctoral study at King’s College London with Prof. Paula Booth before being awarded a BBSRC Future Leader Fellowship in 2016. His main research focus is on “Developing new analytical techniques and protocols for structural biology, particularly in the areas of membrane protein folding, function and drug and lipid interactions”.