Design, synthesis and selection of DNA-encoded small-molecule libraries

Area of Science:

• Biochemistry
• Chemical Biology
• Drug Discovery

Background:

• Biochemical combinatorial techniques like phage display are effective for generating protein ligands.
• Adapting these display technologies for small synthetic molecules remains a significant challenge in drug discovery.

Purpose of the Study:

• To synthesize and interrogate a large-scale DNA-encoded library (DEL) of small molecules.
• To develop methods for selection and deconvolution of DELs.
• To discover novel inhibitors for Aurora A kinase and p38 MAP kinase.

Main Methods:

• Construction of an 800-million-member DNA-encoded library using chemical and enzymatic synthesis.
• Affinity selection for identifying molecules that bind to target proteins.
• DNA sequencing and computational analysis for library deconvolution.

Main Results:

• Successful synthesis and interrogation of the DNA-encoded library.
• Identification of specific small molecule inhibitors for Aurora A kinase.
• Discovery of inhibitors targeting p38 MAP kinase.

Conclusions:

• DNA-encoded libraries represent a powerful platform for discovering small molecule ligands.
• The developed methods enable efficient selection and deconvolution of DELs.
• This approach facilitates the identification of novel drug candidates for therapeutic targets.