Don’t miss this week’s B.S.R.C. Alexander Fleming ERA Chair Scientific Seminar entitled: “Targeting RNA with small molecules” by Paraskevi Gkeka from Integrated Drug Discovery, Molecular Design Sciences, Sanofi, Vitry-sur-Seine, France.
Date: Friday, February 28, 2025, 13:00 pm
Venue: B.S.R.C Fleming Lecture Theatre
RNA molecules are implicated in numerous fundamental biological processes and many human pathologies, such as cancer, neurodegenerative disorders, muscular diseases and bacterial infections. Modulating the mode of action of disease-implicated RNA molecules can lead to the discovery of new therapeutical agents and even address pathologies linked to ‘undruggable’ protein targets. One of the main obstacles that have hampered the development of a rational drug design protocol to target RNA with small molecules is the lack of a comprehensive understanding of the molecular mechanisms at the basis of RNA-small molecule recognition. In the first part of my talk, I will present HARIBOSS, the first curated collection of RNA-SM structures determined by X-ray crystallography, nuclear magnetic resonance spectroscopy and cryo-electron microscopy. HARIBOSS facilitates the exploration of drug-like compounds known to bind RNA, the analysis of ligands and pockets properties and ultimately the development of in silico strategies to identify RNA-targeting small molecules. In the second part of my talk, I will present SHAMAN, a computational technique to identify potential small-molecule binding sites in RNA structural ensembles. SHAMAN enables exploring the conformational landscape of RNA with atomistic molecular dynamics and at the same time identifying RNA pockets in an efficient way with the aid of probes and enhanced-sampling techniques. In our benchmark composed of large, structured riboswitches as well as small, flexible viral RNAs, SHAMAN successfully identified all the experimentally resolved pockets and ranked them among the most favorite probe hotspots. In the last part of my talk, I will shortly present our efforts at Sanofi to use collective human and artificial intelligence to optimize drug discovery.
