Poster abstracts

Poster number 4 submitted by Ali Aldhumani

RNA drug discovery: developing computational models to predict ‘hit’ compounds

Ali H. Aldhumani (Chemistry & Biochemistry, Ohio University), Jennifer V. Hines (Chemistry & Biochemistry, Ohio University)

Abstract:
One solution to the increase in antibiotic resistance is targeting noncoding regulatory RNAs (ncRNAs). ncRNAs may be considered ideal drug targets as they would affect pathogens at the genomic level; most antibiotics currently target pathogens at the protein level. One ncRNA of interest is the T-box riboswitch, which regulates gene expression through transcription termination or translation inhibition and is found primarily in Gram-positive bacteria.1 Previous studies have shown the ability to target structured elements in the T-box riboswitch, for example, using small synthetic compounds2, 3 or readily available commercial compound libraries4. While both these methods of targeting RNA have clear advantages; specifically target-based designs (synthetic compounds) or chemical space (compound libraries), they do pose challenges to experimental resources. We are developing computational prediction models to improve efficiencies in compound screening. We have begun generating 3D grids to predict compound binding characteristics. Using chemoinformatic approaches, we are correlating computational generated binding characteristics to experimental data to develop a pharmacophore model that may predict future ‘hit’ compounds and expand the druggability of the T-box riboswitch.

References:
1. Kreuzer, K. D.; Henkin, T. M. The T-box riboswitch: tRNA as an effector to modulate gene regulation. Microbiol Spectrum 2018, 6 (4), RWR.
2. Liu, J.; Zeng, C.; Hogan, V.; Zhou, S.; Monwar, M. M.; Hines, J. V. Identification of Spermidine Binding Site in T-box Riboswitch Antiterminator RNA. Chem Biol Drug Des 2016, 87 (2), 182.
3. Orac, C. M.; Zhou, S.; Means, J. A.; Boehm, D.; Bergmeier, S. C.; Hines, J. V. Synthesis and stereospecificity of 4,5-disubstituted oxazolidinone ligands binding to T-box riboswitch RNA. J Med Chem 2011, 54 (19), 6786.
4. Frohlich, K. M.; Weintraub, S. F.; Bell, J. T.; Todd, G. C.; Vare, V. Y. P.; Schneider, R.; Kloos, Z. A.; Tabe, E. S.; Cantara, W. A.; Stark, C. J. et al. Discovery of Small-Molecule Antibiotics against a Unique tRNA-Mediated Regulation of Transcription in Gram-Positive Bacteria. ChemMedChem 2019, DOI:10.1002/cmdc.201800744 10.1002/cmdc.201800744.

Keywords: T-Box Riboswitch, ncRNA, Drug Discovery