Advances in MS Based Strategies for Probing Ligand-Target Interactions: Focus on Soft Ionization Mass Spectrometric Techniques.

Guilin Chen,Minxia Fan,Baoqing Sun,Mingquan Guo,Na Li,Ye Liu,Meixian Liu,Jianlin Wu

doi:10.3389/fchem.2019.00703

Abstract

The non-covalent interactions between small drug molecules and disease-related proteins (ligand-target interactions) mediate various pharmacological processes in the treatment of different diseases. The development of the analytical methods to assess those interactions, including binding sites, binding energies, stoichiometry and association-dissociation constants, could assist in clarifying the mechanisms of action, precise treatment of targeted diseases as well as the targeted drug discovery. For the last decades, mass spectrometry (MS) has been recognized as a powerful tool to study the non-covalent interactions of the ligand-target complexes with the characteristics of high sensitivity, high-resolution, and high-throughput. Soft ionization mass spectrometry, especially the electrospray mass spectrometry (ESI-MS) and matrix assisted laser desorption ionization mass spectrometry (MALDI-MS), could achieve the complete transformation of the target analytes into the gas phase, and subsequent detection of the small drug molecules and disease-related protein complexes, and has exerted great advantages for studying the drug ligands-protein targets interactions, even in case of identifying active components as drug ligands from crude extracts of medicinal plants. Despite of other analytical techniques for this purpose, such as the NMR and X-ray crystallography, this review highlights the principles, research hotspots and recent applications of the soft ionization mass spectrometry and its hyphenated techniques, including hydrogen-deuterium exchange mass spectrometry (HDX-MS), chemical cross-linking mass spectrometry (CX-MS), and ion mobility spectrometry mass spectrometry (IMS-MS), in the study of the non-covalent interactions between small drug molecules and disease-related proteins.

Highlights

The life process is closely related to numerous inherent biological macromolecules, such as proteins, peptides, and nucleic acids, which are important components of the biological organisms
Kuzuhara et al (2006) used coldspray ionization (CSI)-mass spectrometry (MS) to study the interactions between the (-)-epigallocatechin gallate (EGCG) and the single-stranded DNA, single-stranded RNA and doublestranded DNA with the green tea extracts, and the results showed that the galactyl and catechin groups in EGCG structure contributed to the binding affinities to nucleic acid molecules
Applications of matrix assisted laser desorption ionization (MALDI)-MS in the Interactions of Small Drug Molecules With Proteins Compared with electrospray ionization (ESI)-MS, MALDI-MS is used much less in the studies of the interactions between the small drug molecules and the biological macromolecules, mainly because of the strong acidic matrix or organic co-solvents commonly used in sample preparation during MALDI-MS analysis, which is easy to cause the dissociation of non-covalent complexes

Summary

Introduction

The life process is closely related to numerous inherent biological macromolecules, such as proteins, peptides, and nucleic acids, which are important components of the biological organisms. This present manuscript summarized and reviewed the applications of the soft ionization MS, especially the ESI-MS and MALDI-MS, in the study of the interactions between small drug molecules and biological macromolecules.

Results

Conclusion