Can In-Silico Computational Virtual Screening of Fragment Libraries Model In-Vitro Biophysical Screening Methods with Similar Results to Identify Novel RNA-Binding Chemical Matter for Treatment of Myotonic Dystrophy?

Abstract

Myotonic Dystrophy is an autosomal dominant trinucleotide repeat expansion disorder caused by a CTG repeat in the 3’ untranslated region of the DMPK gene. These repeats become pathogenic when transcribed into RNA as they form ribonuclear foci comprised of auto complementary CUG hairpin structures, which in turn bind MBNL1, a key RNA splicing regulator. DM1 patients suffer from multisystemic muscle wasting, or myopathy, in muscled areas like arms, forearms, hands, ankles, jaws, tongue, and neck flexors (Ozimski et al., 2020). Utilizing small molecules to target CUG RNA hairpins is a potential tractable mechanism to prevent downstream mis-splicing thereby improving disease phenotype in patients. No published work, on novel small molecule drug discovery or drug repurposing, has shown potent CUG RNA binding with downstream in-vivo splicing rescue. This study shows early hit finding for small molecule binding to CUG RNA hairpins can be achieved using both biophysical methods and computational screening. Utilizing both approaches in conjunction, a statistically significant number (3.2%) of overlapping hits can be selected for further experimental validation.