Docking-based Virtual Screening for the Discovery of RNA-targeting Molecules: Identification of Selective Riboswitch Binding Ligands

Abstract

We present herein one of the very first applications of molecular docking towards the discovery of novel RNA-targeting molecules. Our in-house docking program FITTED was used to perform independ-ent virtual screening campaigns against the TPP, SAM, and FMN riboswitches. Based on the predicted docking scores and poses, between 14 and 20 compounds were selected from commercial libraries and purchased for experimental evaluation of binding to their respective riboswitches by surface plasmon resonance. Promisingly, two compounds displayed highly specific and dose-dependent binding to the TPP riboswitch and FMN riboswitch, with experimentally-determined KDs of 170 μM and 220 μM, re-spectively. This work highlights the promise of modifying and applying docking programs for the dis-covery of nucleic acid- targeting molecules.