Navigating the DNA encoded libraries chemical space

Abstract

DNA-encoded library (DEL) technology is a novel ligand identification strategy that allows the synthesis and screening of unprecedented chemical diversity more efficiently than conventional methods. However, no reports have been published to systematically study how to increase the diversity and improve the molecular property space that can be covered with DEL. This report describes the development and application of eDESIGNER, an algorithm that comprehensively generates all possible library designs, enumerates and profiles samples from each library and evaluates them to select the libraries to be synthesized. This tool utilizes suitable on-DNA chemistries and available building blocks to design and identify libraries with a pre-defined molecular weight distribution and maximal diversity compared with compound collections from other sources.

Orthogonal DNA barcodes enable the high-throughput screening of sequence-defined polymers

“…Such DNA-encoded libraries (DELs) have already greatly facilitated high-throughput screening for small molecules, and they are now a mainstay in drug discovery. 12 DELs encrypt each small molecule library member with a DNA code 13 that can be amplified and sequenced from very small concentrations (<10 -15 nM) using the polymerase chain reaction (PCR); [14][15][16][17][18] DEL synthesis 16 typically requires organic reactions that are orthogonal to DNA-ligation chemistry, and may not provide the high coupling yields necessary for making sequence-defined polymers. Solid-phase phosphoramidite synthesis, on the other hand, can afford high-purity DNA strands 19 up to 200 nucleotides long, and is even used to produce FDA-approved oligonucleotide therapeutics.…”

National Institutes of Health (NIH) Workshop on Reaction Informatics

“…They have developed and applied eDESIGNER, an algorithm that comprehensively generates all possible library designs, enumerates and profiles samples from each library and evaluates them to select the libraries to be synthesized. 232 This tool uses suitable on-DNA chemistries and available building blocks to design and identify libraries with a predefined molecular weight distribution and maximal diversity compared with compound collections from other sources.…”

Exploration of the chemical space of DNA-encoded libraries

“…For the generation of chemical space of DELs, the eDESIGNER 14 tool was used. At first, based on the list of the most efficient DNA-compatible reactions encoded in the tool (see Supporting Information of respective article 14 ) and a user-provided list of BBs, it generates a special set of instructions for DEL compound enumeration called libDESIGNs.…”

“…For the generation of chemical space of DELs, the eDESIGNER 14 tool was used. At first, based on the list of the most efficient DNA-compatible reactions encoded in the tool (see Supporting Information of respective article 14 ) and a user-provided list of BBs, it generates a special set of instructions for DEL compound enumeration called libDESIGNs. Each libDESIGN contains information about the starting headpiece (the whole DNA part for computational convenience is formally represented as a 13 C atom), the reaction types, and BBs which will be used in them, as well as deprotection reactions for the final stage of DEL generation.…”

“…Since DEL technology is actively being developed and new methodologies for DEL synthesis were being elaborated, the aforementioned pioneering work no longer reflects the status quo. This work is focused on the generation of possible DELs from commercially available BBs using a tool for DELs generation called eDesigner 14 . Since screening thousands of DELs containing billions of compounds is unfeasible, we suggest choosing the so-called "golden" DEL(s) that covers the chemical space of biologically tested compounds to the highest extent.…”