Poster abstracts
Poster number 11 submitted by Grace Arhin
Identification of compounds targeting NPSL2 - a regulatory element in the oncomiR-1 RNA: A combined STD-NMR and molecular modelling approach
Grace Arhin (University of Michigan, Biophysics ), Sarah Keane (University of Michigan, Chemistry and Biophysics)
Abstract:
MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally repress gene expression through base pairing with complementary sequences on target messenger RNAs. The miRNA genes are transcribed as primary transcripts which are enzymatically processed to form precursor hairpins and finally mature duplexes through stepwise processing by Drosha and Dicer enzyme complexes. Due to the important role of microRNA-regulated gene expression, the regulation of microRNA biogenesis must be strictly controlled. Evidence suggests that RNA-binding proteins (RBPs), precursor structure and small molecule interactions can post-transcriptionally regulate mature miRNA formation. OncomiR-1 is a polycistronic miRNA (encodes six different miRNAs) known to be overly expressed in multiple cancers. Within oncomiR-1, a non-miRNA element known as NPSL2 has been hypothesized to serve as a linchpin for a large-scale conformational rearrangement that regulates the Drosha-mediated cleavage of pri-miRNA-92a. We hypothesize that stabilizing the NPSL2 structure will prevent this rearrangement. We have conducted a virtual screen on the ZINC library of diverse chemical compounds against NPSL2, with a focus on identifying small molecules that bind to and stabilize the NPSL2 structure. Using saturation transfer difference (STD) NMR, we have tested and validated binding of hits from the virtual screening campaign against NPSL2. Collectively, we have established a platform integrating in silico and an experimental screening approach for efficient discovery of ligands targeting NPSL2. We are now testing to see if these “hits” function to modulate the Drosha processing of miRNA 92a.
Keywords: Micro-RNAs, Virtual Screening, STD-NMR