DNA-Encoded Chemical Libraries: Advancing beyond Conventional Small-Molecule Libraries

Abstract

DNA-encoded chemical libraries (DECLs) represent a promising tool in drug discovery. DECL technology allows the synthesis and screening of chemical libraries of unprecedented size at moderate costs. In analogy to phage-display technology, where large antibody libraries are displayed on the surface of filamentous phage and are genetically encoded in the phage genome, DECLs feature the display of individual small organic chemical moieties on DNA fragments serving as amplifiable identification barcodes. The DNA-tag facilitates the synthesis and allows the simultaneous screening of very large sets of compounds (up to billions of molecules), because the hit compounds can easily be identified and quantified by PCR-amplification of the DNA-barcode followed by high-throughput DNA sequencing. Several approaches have been used to generate DECLs, differing both in the methods used for library encoding and for the combinatorial assembly of chemical moieties. For example, DECLs can be used for fragment-based drug discovery, displaying a single molecule on DNA or two chemical moieties at the extremities of complementary DNA strands. DECLs can vary substantially in the chemical structures and the library size. While ultralarge libraries containing billions of compounds have been reported containing four or more sets of building blocks, also smaller libraries have been shown to be efficient for ligand discovery. In general, it has been found that the overall library size is a poor predictor for library performance and that the number and diversity of the building blocks are rather important indicators. Smaller libraries consisting of two to three sets of building blocks better fulfill the criteria of drug-likeness and often have higher quality. In this Account, we present advances in the DECL field from proof-of-principle studies to practical applications for drug discovery, both in industry and in academia. DECL technology can yield specific binders to a variety of target proteins and is likely to become a standard tool for pharmaceutical hit discovery, lead expansion, and Chemical Biology research. The introduction of new methodologies for library encoding and for compound synthesis in the presence of DNA is an exciting research field and will crucially contribute to the performance and the propagation of the technology.

DNA‐encoded chemical libraries – achievements and remaining challenges

“…It has previously been noted that the number and quality of building blocks greatly contributes to library performance [13]. On the positive side, thousands of building blocks (e.g., carboxylic acids, amines, alkynes, azides, sulphonyl chlorides, boronates) are now commercially available at affordable prices, thus facilitating library construction activities even in the academic environment.…”

Extending accessible chemical space for the identification of novel leads

“…Regardless, parallel synthesis and other combinatorial techniques have become established approaches and the 'classical' diversity concept that came along with combinatorial approaches has left its mark on library design. Moreover, in recent years, the generation of 'classical' chemical diversity applying established combinatorial reactions has been experiencing a renaissance, especially through the introduction of DNA-encoded libraries [22,23]. These libraries consist of combinatorial compounds that are conjugated through chemical linkers with single-or double-stranded DNA fragments that serve as unique compound identifiers, analogously to bar codes, as illustrated in Figure 3.…”

Risk mitigation in academic drug discovery

“…This results in the problem that projects can be conservative when it comes to adopting disruptive technologies, such as DNA-encoded libraries, for hit finding as they are associated with a possible whole slew of new and unknown risks. [18] However, the chance of charting unseen chemical space with such disruptive methods may make their use worth the effort in the longer term. A similar argument is true for the development of improved animal models, as they may well directly lead to a better understanding of the disease and improved efficacy of new therapies.…”