Abstract
Guanine-rich sequences forming G-quadruplexes (GQs) are present in several genomes, ranging from viral to human. Given their peculiar localization, the induction of GQ formation or GQ stabilization with small molecules represents a strategy for interfering with crucial biological functions. Investigating the recognition event at the molecular level, with the aim of fully understanding the triggered pharmacological effects, is challenging. Native electrospray ionization mass spectrometry (ESI-MS) is being optimized to study these noncovalent assemblies. Quantitative parameters retrieved from ESI-MS studies, such as binding affinity, the equilibrium binding constant, and sequence selectivity, will be overviewed. Computational experiments supporting the ESI-MS investigation and boosting its efficiency in the search for GQ ligands will also be discussed with practical examples. The combination of ESI-MS and in silico techniques in a hybrid high-throughput-screening workflow represents a valuable tool for the medicinal chemist, providing data on the quantitative and structural aspects of ligand–GQ interactions.
Highlights
Nucleic acids are flexible species that can fold into secondary structures consisting in a peculiar three-dimensional arrangement when in solution
To provide support to the medicinal chemist in the search for GQ ligands, analytical techniques should unambiguously allow the measurement of the GQ over double stranded deoxyribonucleic acid (DNA) (dsDNA) selectivity and provide insights about binding sites and the mode of interaction.[59]
A brief overview will be provided anyway in the following to put the subsequent discussion in the right context, and the interested reader is invited to refer to other reviews that are more focused on biophysical techniques.[7,33,60,61]
Summary
Nucleic acids are flexible species that can fold into secondary structures consisting in a peculiar three-dimensional arrangement when in solution. The final step of this mechanism leads to the formation of desolvated ions in the gas phase; in the so-called “charge residue” model, a droplet contains a single molecule of the analyte ion, which in the current case is represented by a macromolecule and, a nucleic acid sequence potentially complexed with a ligand.[28,60] As will be discussed more in detail in the following, by tuning voltages, temperatures, and pressures in the spectrometer, the opportune removal of solvent and counterions, which are respectively termed desolvation and declustering, can be achieved to optimize the signal of the investigated species.[60,78] In these conditions, minimal fragmentation occurs, and as a result noncovalent interactions are not altered during the ESI process.[28]. This technique, as will be discussed in the following, can potentially provide information on the binding mode, sequence selectivity, and the ligand binding affinity.[34]
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