Toward the Chemoenzymatic Synthesis of DNA-Encoded Libraries

TL;DR

This paper explores using enzymes to expand the range of chemical reactions possible in DNA-encoded libraries for drug discovery.

Contribution

The paper introduces enzymatic catalysis as a novel approach to enhance DNA-encoded library synthesis.

Findings

Enzymatic catalysis offers DNA compatibility for on-DNA synthesis.

This method can expand the chemical space accessible through DNA-encoded libraries.

Abstract

DNA-encoded libraries (DELs) have become a powerful platform
in
drug discovery, practiced both by the pharmaceutical industry and
academia. Each small molecule contained in a DEL is covalently linked
to a DNA tag which serves as an amplifiable barcode facilitating binder
identification. However, the chemical diversity accessible in DELs
remains limited by the need to perform reactions under conditions
that preserve the integrity of the DNA tag. Additionally, chemical
reactions must proceed with high efficiency and selectivity to minimize
side products and unreacted starting materials, which cannot be removed
and may hamper hit identification. Consequently, expanding the DEL
chemical space requires the development of methods that combine high
reaction performance with DNA compatibility. In this outlook, we highlight
the potential of enzymatic catalysis for on-DNA synthesis, which offers
a promising route to expand DEL-accessible chemical space.

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