Identification and Partial Structural Characterization of Mass Isolated Valsartan and Its Metabolite with Messenger Tagging Vibrational Spectroscopy
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Recent advances in the coupling of vibrational spectroscopy with mass spectrometry create new opportunities for the structural characterization of metabolites with great sensitivity. Previous studies have demonstrated this scheme on 300 K ions using very high power free electron lasers in the fingerprint region of the infrared. Here we extend the scope of this approach to a single investigator scale as well as extend the spectral range to include the OH stretching fundamentals. This is accomplished by detecting the IR absorptions in a linear action regime by photodissociation of weakly bound N2 molecules, which are attached to the target ions in a cryogenically cooled, rf ion trap. We consider the specific case of the widely used drug Valsartan and two isomeric forms of its metabolite. Advantages and challenges of the cold ion approach are discussed, including disentangling the role of conformers and the strategic choices involved in the selection of the charging mechanism that optimize spectral differentiation among candidate structural isomers. In this case, the Na+ complexes are observed to yield sharp resonances in the high frequency NH and OH stretching regions, which can be used to easily differentiate between two isomers of the metabolite.
KeywordsVibrational spectroscopy Mass spectrometry IR-spectroscopy Metabolomics Metabolite Drug discovery Conformer differentiation
M.A.J. thanks the National Science Foundation for support under grant number CHE-1465100. This work was supported in part by the Yale University Faculty of Arts and Sciences High Performance Computing Facility (and staff). A.B. acknowledges financial support from the National Science Foundation through the HBCU-UP award no. 1505095. We also thank Nan Yang and Chinh Duong for their work on the updated instrumental capabilities utilized in this experiment (Figure 2).
- 13.Nakashima, A., Kawashita, H., Masuda, N., Saxer, C., Niina, M., Nagae, Y., Iwasaki, K.: Identification of cytochrome P450 forms involved in the 4-hydroxylation of valsartan, a potent and specific angiotensin II receptor antagonist, in human liver microsomes. Xenobiotica 35, 589–602 (2005)CrossRefGoogle Scholar
- 18.Leavitt, C.M., Wolk, A.B., Fournier, J.A., Kamrath, M.Z., Garand, E., Van Stipdonk, M.J., Johnson, M.A.: Isomer-specific IR-IR double resonance spectroscopy of D2-tagged protonated dipeptides prepared in a cryogenic ion trap. J. Phys. Chem. Lett. 3, 1099–1105 (2012)Google Scholar
- 23.Myshakin, E.M., Jordan, K.D., Sibert, E.L., Johnson, M.A.: Large anharmonic effects in the infrared spectra of the symmetrical CH3NO2 -·(H2O) and CH3CO2 -·(H2O) complexes. J. Chem. Phys. 119, 10138–10145 (2003)Google Scholar
- 28.Gord, J.R., Hewett, D.M., Hernandez-Castillo, A.O., Blodgett, K.N., Rotondaro, M.C., Varuolo, A., Kubasik, M.A., Zwier, T.S.: Conformation-specific spectroscopy of capped, gas-phase Aib oligomers: tests of the Aib residue as a 310-helix former. Phys. Chem. Chem. Phys. 18, 25512–25527 (2016)CrossRefGoogle Scholar
- 29.Bush, M.F., Forbes, M.W., Jockusch, R.A., Oomens, J., Polfer, N.C., Saykally, R.J., Williams, E.R.: Infrared spectroscopy of cationized lysine and ε-N-methyllysine in the gas phase: effects of alkali-metal ion size and proton affinity on zwitterion stability. J. Phys. Chem. A 111, 7753–7760 (2007)CrossRefGoogle Scholar
- 30.Huan, T., Tang, C., Li, R., Shi, Y., Lin, G., Li, L.: MyCompoundID MS/MS search: metabolite identification using a library of predicted fragment-ion-spectra of 383,830 possible human metabolites. Anal. Chem. 87, 10619–10626 (2015)Google Scholar
- 31.Awad, H., El-Aneed, A.: Enantioselectivity of mass spectrometry: challenges and promises. Mass Spectrom. Rev. 32, 466–483 (2013)Google Scholar