Finding the Right Candidate for the Right Position: A Fast NMR-Assisted Combinatorial Method for Optimizing Nucleic...

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• Optimizing lead compounds into selective drug binders is a costly and lengthy process in drug discovery.
• Multivalent polyamine scaffolds are promising for DNA/RNA ligand development.
• Fragment-based drug design requires efficient methods for library synthesis and screening.

Purpose of the Study:

• To present a novel fragment-based combinatorial strategy for optimizing multivalent polyamine scaffolds as DNA/RNA ligands.
• To demonstrate a rapid method for generating and testing regioisomer libraries.
• To evaluate the utility of NMR spectroscopy in high-throughput screening of complex compound mixtures.

Main Methods:

• A fragment-based combinatorial strategy was employed for scaffold optimization.
• Microdialysis assays combined with isotope labeling and NMR experiments were used for compound evaluation.
• 100 novel kanamycin-B derivatives were synthesized and screened for selective binding.

Main Results:

• The developed protocol provides rapid access to diverse regioisomer libraries.
• NMR methodology proved effective for detecting and quantifying complex mixtures of similar compounds.
• Selective binding to the ribosomal decoding A-Site sequence was evaluated for the synthesized derivatives.

Conclusions:

• The presented NMR-based approach offers a valuable, high-throughput alternative for lead optimization.
• The study provides insights into structural requirements for selective A-site recognition.
• This strategy accelerates the development of potent and selective DNA/RNA ligands.