Using density functional theory to rationalise the mass spectral fragmentation of maraviroc and its metabolites

Tandem mass spectrometry (MS/MS) is widely used for the identification of metabolites at all stages of the pharmaceutical discovery and development process. The assignment of ions in the product ion spectra can be time‐consuming and hence delay feedback of results that may influence the direction of a project. A deeper understanding of the processes involved in generation of the product ions formed via collision‐induced dissociation may allow development of chemically intelligent software to aid spectral interpretation. Current commercially available spectral interpretation software takes a mainly arithmetical approach resulting in extensive lists of numerically plausible ions, many of which may not be chemically feasible. In this study, high‐resolution MS/MS spectra were obtained for maraviroc and two of its synthetic metabolites, and structures for the product ions proposed. Density functional theory (DFT) based on in silico modelling was undertaken to investigate whether the fragmentation observed was potentially a result of bond lengthening (and hence weakening) as a consequence of protonation of the molecule at the most thermodynamically stable site(s). It was determined that for all three compounds, where the product ions resulted from simple bond cleavages (not rearrangements), the bonds that cleaved had been calculated to elongate after protonation. It was also noted that the protonated molecule may represent a mixture of singly charged protonated species and that the most basic sites in the molecule may not necessarily be the most thermodynamically stable for protonation. Copyright © 2010 John Wiley & Sons, Ltd.