RNA-targeted Drug Design: Impact of pH on Fragment-Based Ligand Discovery
Abstract
RNA molecules play integral roles in biological processes and offer alternative drug targets beyond proteins. Protonated nucleotides play crucial roles in RNA structural and functional dynamics, influencing ligand binding and recognition. pH-dependent structural changes have been observed in the T-box riboswitch Antiterminator (AM) element and the stem-loop II motif of SAR-CoV and CoV-2 RNAs, indicating potential nucleobase protonation events (Md I. Hossan, J.V. Hines, unpublished results). This study investigates pH effects on these RNAs and their interactions with small molecule fragments, combining crystal structure analysis, experimental techniques, and computational docking. The investigation identifies protonated nucleobases in RNA crystal structures, based on a representative dataset, and characterizes them by hydrogen bonding, salt bridges, cation-pi interactions, and root mean square deviation values upon optimization. Test fragment library docking reveals notable binding affinities of SKB-172 and SKB-166 with AM (Glide Emodel scores: -75.538 kcal/mol and -57.852 kcal/mol, respectively). While stereoselectivity is somewhat limited, docking simulations and experimental screening at pH 6.5 show a strong correlation, suggesting a potential synergistic action of SKB-172 and SKB-166.
Keywords:
Virtual Protonation, root mean square deviation (rmsd), Molecular docking, Fragment-based screening, Chemistry and Biochemistry.
Status
Graduate
Department
Chemistry & Biochemistry
College
College of Arts and Sciences
Campus
Athens
Faculty Mentor
HINES, JENNIFER
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
RNA-targeted Drug Design: Impact of pH on Fragment-Based Ligand Discovery
RNA molecules play integral roles in biological processes and offer alternative drug targets beyond proteins. Protonated nucleotides play crucial roles in RNA structural and functional dynamics, influencing ligand binding and recognition. pH-dependent structural changes have been observed in the T-box riboswitch Antiterminator (AM) element and the stem-loop II motif of SAR-CoV and CoV-2 RNAs, indicating potential nucleobase protonation events (Md I. Hossan, J.V. Hines, unpublished results). This study investigates pH effects on these RNAs and their interactions with small molecule fragments, combining crystal structure analysis, experimental techniques, and computational docking. The investigation identifies protonated nucleobases in RNA crystal structures, based on a representative dataset, and characterizes them by hydrogen bonding, salt bridges, cation-pi interactions, and root mean square deviation values upon optimization. Test fragment library docking reveals notable binding affinities of SKB-172 and SKB-166 with AM (Glide Emodel scores: -75.538 kcal/mol and -57.852 kcal/mol, respectively). While stereoselectivity is somewhat limited, docking simulations and experimental screening at pH 6.5 show a strong correlation, suggesting a potential synergistic action of SKB-172 and SKB-166.