Applications of ESI-MS in drug discovery: interrogation of noncovalent complexes

Abstract

For many years, analytical mass spectrometry has had numerous supporting roles in the drug development process, including the assessment of compound purity; quantitation of absorption, distribution, metabolism and excretion; and compound-specific pharmacokinetic analyses. More recently, mass spectrometry has emerged as an effective technique for identifying lead compounds on the basis of the characterization of noncovalent ligand-macromolecular target interactions. This approach offers several attractive properties for screening applications in drug discovery compared with other strategies, including the small quantities of target and ligands required, and the capacity to study ligands or targets without having to label them. Here, we review the application of electrospray ionization mass spectrometry to the interrogation of noncovalent complexes, highlighting examples from drug discovery efforts aimed at a range of target classes.

Exploring metallodrug–protein interactions by mass spectrometry: comparisons between platinum coordination complexes and an organometallic ruthenium compound

“…metallodrugprotein adducts. Although ESI MS is not a quantitative technique, it can be used to screen multicomponent systems, providing a semiquantitative description of the abundance of the species in solution [42]. Typically, ESI MS has been applied to establish the affinity of multiple potential ligands for a single macromolecular target; however, related procedures have been used to study ligand binding to (and affinity for) a protein mixture [38].…”

Stepwise evolution of protein native structure with electrospray into the gas phase, 10 −12 to 10 2 s

“…Depending on experimental conditions and nature of the complex, a time window of Ϸ10 Ϫ3 s can be available for complex detection in the mass spectrometer. Then ESI MS can give information on complex stoichiometry and, after complex dissociation (MS/MS), reveal the identity of binding partners (6)(7)(8)(9)(10)(11).…”

Characterization of primaquine imidazolidin-4-ones with antimalarial activity by electrospray ionization-ion trap mass spectrometry

“…to time-of-flight mass spectrometry (ToF-MS) [31,32,35]. ESI-MS n studies of antimalarial compounds as bisthiazolium or quinolines can be found on reports by Nicolas et al [38] or Smyth et al and O'Donnell et al [34,39], respectively.…”