Physicochemical Principles Driving Small Molecule Binding to RNA

The possibility of using RNA-targeting small molecules to treat diseases is gaining traction as the next frontier of drug discovery and development. The chemical characteristics of small molecules that bind to RNA are still relatively poorly understood, particularly in comparison to protein-targeting small molecules. To fill this gap, we have generated an unprecedented amount of RNA-small molecule binding data, and used it to derive physicochemical rules of thumb that could be used to define areas of chemical space enriched for RNA binders - the Small molecules Targeting RNA (STaR) rules of thumb. These rules have been applied to publicly available RNA-small molecule datasets and found to be largely generalizable. Furthermore, a number of patented RNA-targeting compounds and FDA-approved compounds also pass these rules, as well as key RNA binding approved drug case studies including Risdiplam. We anticipate this work will significantly accelerate the exploration of the RNA-targeted chemical space, towards unlocking RNA’s potential as a small molecule drug target. Graphical Abstract