Scanning Protein Surfaces with DNA‐Encoded Libraries

Abstract

Understanding the ligandability of a target protein, defined as the capability of a protein to bind drug‐like compounds on any site, can give important stimuli to drug‐development projects. For instance, inhibition of protein–protein interactions usually depends on the identification of protein surface binders. DNA‐encoded chemical libraries (DELs) allow scanning of protein surfaces with large chemical space. Encoded library selection screens uncovered several protein–protein interaction inhibitors and compounds binding to the surface of G protein‐coupled receptors (GPCRs) and kinases. The protein surface‐binding chemotypes from DELs are predominantly chemically modified and cyclized peptides, and functional small‐molecule peptidomimetics. Peptoid libraries and structural peptidomimetics have been less studied in the DEL field, hinting at hitherto less populated chemical space and suggesting alternative library designs. Roughly a third of bioactive molecules evolved from smaller, target‐focused libraries. They showcase the potential of encoded libraries to identify more potent molecules from weak, for example, fragment‐like, starting points.

DNA-Compatible Suzuki-Miyaura Cross-Coupling Reaction of Aryl Iodides With (Hetero)Aryl Boronic Acids for DNA-Encoded Libraries

“…DNA-Encoded Library (DEL) technology is based on the concept from Brenner and Lerner ( Brenner and Lerner 1992 ) and it is commonly used in the pharmaceutical industry to identify novel chemical matter that binds and modulates specific protein targets ( Melkko et al, 2004 ; Melkko et al, 2007 ; Clark et al, 2009 ; Kleiner et al, 2011 ; Franzini et al, 2014 ; Salamon et al, 2016 ; Goodnow et al, 2017 ; Favalli et al, 2018 ; Neri and Lerner 2018 ; Ottl et al, 2019 ; Yuen et al, 2019 ; Zhao et al, 2019 ; Kunig et al, 2021 ; Shi et al, 2021 ). During the past decade, the use of DEL technology provided a great opportunity to identify drug-like compounds that can bind selectively to a variety of target proteins ( Deng et al, 2012 ; Gentile et al, 2012 ; Disch et al, 2013 ; Samain et al, 2015 ; Seigal et al, 2015 ; Harris et al, 2016 ; Belyanskaya et al, 2017 ; Dawadi et al, 2020 ; Chamakuri et al, 2021 ).…”

Recent advances in DNA-encoded dynamic libraries

“…In the past two decades, the emergence of the DNA-encoded library (DEL) technology, also called DELT, replaced spatial encoding with DNA encoding in chemical libraries, thus overcoming the throughput limit of traditional HTS and being much more affordable and accessible to researchers. [2][3][4][5][6][7][8][9][10][11] For instance, many companies and institutions are offering DEL selection services; premade DEL kits 12 for direct use in selections and reagent kits 13 for custom DEL synthesis are also available to meet the needs of individual researchers. Furthermore, with the recent expansion of DNA-/DEL-compatible reaction toolkit, 2,6,7,[14][15][16] DELs can access much greater chemical space, which has been a major driver for its adoption in the pharmaceutical industry.…”

Evolution of the Selection Methods of DNA-Encoded Chemical Libraries

“…There are four major components of the DEL technology: chemistry, encoding, selection, and hit decoding/data analysis. The recent literature has provided many excellent reviews on these topics. ,,− However, DEL research is heavily biased toward library synthesis/chemistry, and an underexplored aspect is the selection methods. DEL selection is fundamentally a massive binding assay.…”