Prediction of Mass Spectral Response Factors from Predicted Chemometric Data for Druglike Molecules

Cramer, C. J.; Johnson, J. L.; Kamel, A.
J. Am. Soc. Mass Spectrom. 2017, 28, 285 (doi:10.1007/s13361-016-1536-4).

A method is developed for the prediction of mass spectral ion counts of druglike molecules using in silico calculated chemometric data. Various chemometric data, including polar and molecular surface areas, aqueous solvation free energies, and gas-phase and aqueous proton affinities were computed and a statistically significant relationship between measured mass spectral ion counts and the combination of aqueous proton affinity and total molecular surface area was identified. In particular, through multilinear regression of ion counts on predicted chemometric data, we find that log₁₀(MS ion counts) = –4.824 + c₁ • PA + c₂ • SA where PA is the aqueous proton affinity of the molecule computed at the SMD(aq)/M06-L/MIDI!//M06-L/MIDI! level of electronic structure theory, SA is the total surface area of the molecule in its conjugate base form, and c₁ and c₂ have values of –3.912 x 10^–2 mol kcal^–1 and 3.682 x 10^–3 Å^–2. On a 66 molecule training set, this regression exhibits a multiple R value of 0.791 with p values for the intercept, c₁, and c₂ of 1.4 x 10^–3, 4.3 x 10^–10, and 2.5 x 10^–6, respectively. Application of this regression to an 11-molecule test set provides a good correlation of prediction with experiment (R = 0.905) albeit with a systematic underestimation of about 0.2 log units. This method may prove useful for semiquantitative analysis of drug metabolites for which MS response factors or authentic standards are not readily available.