Designing small molecules targeting a cryptic RNA binding site through base displacement.

ABSTRACT: Most RNA-binding small molecules have limited solubility, weak affinity and/or lack of specificity, restricting the medicinal chemistry often required for lead compound discovery. We reasoned that conjugation of these unfavorable ligands to a suitable 'host' molecule can solubilize the 'guest' and deliver it site-specifically to an RNA of interest to resolve these issues. Using this framework, we designed a small-molecule library that was hosted by cobalamin (Cbl) to interact with the Cbl riboswitch through a common base displacement mechanism. Combining in vitro binding, cell-based assays, chemoinformatic modeling and structure-based design, we unmasked a cryptic binding site within the riboswitch that was exploited to discover compounds that have affinity exceeding the native ligand, ant

SUBMITTER: Olenginski LT 

PROVIDER: S-EPMC12688817 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature