Elucidation of drug metabolite structural isomers using molecular modeling coupled with ion mobility mass spectrometry.

Reading, Eamonn, Munoz-Muriedas, Jordi, Roberts, Andrew D, Dear, Gordon J, Robinson, Carol V and Beaumont, Claire (2016) Elucidation of drug metabolite structural isomers using molecular modeling coupled with ion mobility mass spectrometry. Analytical Chemistry, 2273–2280. (doi:10.1021/acs.analchem.5b04068).

Abstract

Ion mobility-mass spectrometry (IM-MS) in combination with molecular modelling 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 characterisation including impurity profiling and degradation chemistry. However, the conformational behaviour of drug molecules and their metabolites in the gas phase is poorly understood. Here the gas phase conformational space of drug and drug-like molecules has been investigated 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 modelling 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 modelling 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 modelling can inform on the identity of drug metabolites and highlight the limitations of this approach in differentiating structural isomers.

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Contributors

Author: Eamonn Reading

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