Assessing Physicochemical Properties of Drug Molecules via Microsolvation Measurements with Differential Mobility Spectrometry

Abstract

The microsolvated state of a molecule, represented by its interactions with only a small number of solvent molecules, can play a key role in determining the observable bulk properties of the molecule. This is especially true in cases where strong local hydrogen bonding exists between the molecule and the solvent. One method that can probe the microsolvated states of charged molecules is differential mobility spectrometry (DMS), which rapidly interrogates an ion’s transitions between a solvated and desolvated state in the gas phase (i.e., few solvent molecules present). However, can the results of DMS analyses of a class of molecules reveal information about the bulk physicochemical properties of those species? Our findings presented here show that DMS behaviors correlate strongly with the measured solution phase pKa and pKb values, and cell permeabilities of a set of structurally related drug molecules, even yielding high-resolution discrimination between isomeric forms of these drugs. This is due to DMS’s ability to separate species based upon only subtle (yet predictable) changes in structure: the same subtle changes that can influence isomers’ different bulk properties. Using 2-methylquinolin-8-ol as the core structure, we demonstrate how DMS shows promise for rapidly and sensitively probing the physicochemical properties of molecules, with particular attention paid to drug candidates at the early stage of drug development. This study serves as a foundation upon which future drug molecules of different structural classes could be examined.

Recommendations for reporting ion mobility Mass Spectrometry measurements

“…The development of FAIMS science since the introduction of these ion types in early work by Guevremont has brought forward a deeper understanding and re‐evaluation of these definitions in several aspects. First, all “ion types” are actually “ion‐gas pair” types—the same ions can assume different types in different gases based upon the ion/molecule interactions between these species (Barnett et al, ; Levin et al, ; Campbell, Zhu, & Hopkins, ; Liu et al, ; Liu et al, ). Generally, increasing the mass and polarizability of gas molecules shifts ions from type C to B to A.…”

Analyzing Glycopeptide Isomers by Combining Differential Mobility Spectrometry with Electron- and Collision-Based Tandem Mass Spectrometry

“…How could these sites of protonation influence the DMS separation (or lack thereof) for the glycopeptides studied here? For the case of the separated doubly protonated species, the more negative CV shift by the MUC5AC-13 isomer suggests that it binds more strongly with the acetonitrile vapor added to the DMS cell than does the MUC5AC-3 isomer [34][35][36]. When considering the structural variation between isomers that could cause such a CV shift, the presence of possible intramolecular hydrogen bonds (IMHBs) in the MUC5AC-3 isomer that internally solvate a site of protonation could be proposed (vide infra).…”

An Intrinsic Hydrophobicity Scale for Amino Acids and Its Application to Fluorinated Compounds

“…Here,wesuggest an alternative hydrophobicity ranking that is obtained by studying the interaction of amino acids in the clean-room environment of the gas phase.A lthough it may appear counterintuitive at first glance,g as-phase conditions are particularly suitable for such investigations,s ince the underlying relative permittivity in av acuum (e r = 1) closely resembles that of the protein interior [14] (e r = 6-7). [15] Our study utilizes the gas-phase technique of ion mobility mass spectrometry (IM-MS), which separates ions according to their mass-to-charge ratio (m/z)a sw ell as their size and shape. [15] Our study utilizes the gas-phase technique of ion mobility mass spectrometry (IM-MS), which separates ions according to their mass-to-charge ratio (m/z)a sw ell as their size and shape.…”