Combining Electrospray Mass Spectrometry (ESI-MS) and Computational Techniques in the Assessment of G-Quadruplex Ligands: A Hybrid Approach to Optimize Hit Discovery.
Giovanni RibaudoAlberto OngaroErika OselladoreMaurizio MemoAlessandra GianoncelliPublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- ms ms
- mass spectrometry
- liquid chromatography
- high resolution
- capillary electrophoresis
- high performance liquid chromatography
- gas chromatography
- multiple sclerosis
- endothelial cells
- electronic health record
- sars cov
- small molecule
- tandem mass spectrometry
- molecular dynamics
- machine learning
- molecular dynamics simulations
- artificial intelligence
- drug discovery
- aqueous solution