Poster abstracts
Poster number 6 submitted by Deborah Amesaki
RNA-Targeted Drug Design: Impact of pH on Fragment-Based Ligand Discovery
Deborah K. Amesaki (Department of Chemistry & Biochemistry, Ohio University), Md Ismail Hossain, Emily A. Fairchild (Department of Chemistry & Biochemistry, Ohio University), Jennifer V. Hines (Department of Chemistry & Biochemistry, Ohio University)
Abstract:
Regulatory noncoding RNA plays an essential role in bacteria, highlighting the significance of RNA as a target for antibacterial development amidst growing concerns over antibiotic resistance. Effective targeting of the RNA requires a knowledge of all the factors that can affect RNA structure, including nucleobase protonation. Nucleobase protonation of A or C can occur when the local environment results in a pKa shift towards neutrality. This study investigates possible nucleobase protonation effects on the bacterial T box riboswitch by combining structure analysis, computational docking and experimental techniques. Based on analysis of crystallographic structure data and in silico protonation, we have identified nucleobases in the T box riboswitch that are consistent with protonation. To explore possible ligand-binding interactions and the effect of nucleobase protonation, we computationally docked fragment and small molecule libraries to the antiterminator and discriminator regions of the T box riboswitch. Analysis of docking data using Principal Component Analysis (PCA) and clustering methods results in 4 clusters. A set of fragments and compounds clustered with known inhibitors of the riboswitch and will be prioritized for ligand binding assays to test as potential hits.
Keywords: Regulatory noncoding RNA, in silico protonation, Fragment-Based Ligand Discovery