Poster abstracts

Poster number 107 submitted by Ali Aldhumani

RNA drug discovery: optimizing chemoinformatic analysis workflow

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

Abstract:
Targeting noncoding regulatory RNA is an emerging field of drug discovery with successful examples in targeting specific small bulges and other structured regions with small molecules. A continued challenge, however, is the specific targeting of larger RNA motifs that are less structured and more flexible. The antiterminator element in the T-box riboswitch is one example. The T-box riboswitch regulates gene expression by transcription antitermination or inhibition of translation initiation and is a good target for antibacterial drug discovery.1 The antiterminator element contains a highly conserved 14 nucleotide sequence and serves an essential role in the riboswitch function. Based on prior results,2 we are optimizing chemoinformatic workflows combining experimental results from screening assays with molecular modeling to identify new ligand scaffolds with improved activity. Utilizing the Schrödinger suite of software, we are developing a pharmacophore binding model for the antiterminator by exploring ligand docking to multiple RNA conformers. Using the Glide function in Maestro, a grid is generated of the antiterminator (NMR derived structure), to which a model compound library (NIH Natural Products Repository IV) is docked. Chemoinformatic analysis of docking results and experimental data to determine quantitative structure-activity relationships will assist in predicting other compounds of interest and provide further insight of 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-0028-2018.
2. (a) 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 Design 2016, 87, 182-189; (b) Orac, C. M.; Zhou, S.; Means, J. A.; Boehme, 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, 6786-6795.

Keywords: T-box riboswitch , drug discovery, ncRNA