Design and Development of a Technology Platform for DNA-Encoded Library Production and Affinity Selection

Abstract

<jats:p> DNA-encoded libraries (DELs) have emerged as an efficient and cost-effective drug discovery tool for the exploration and screening of very large chemical space using small-molecule collections of unprecedented size. Herein, we report an integrated automation and informatics system designed to enhance the quality, efficiency, and throughput of the production and affinity selection of these libraries. The platform is governed by software developed according to a database-centric architecture to ensure data consistency, integrity, and availability. Through its versatile protocol management functionalities, this application captures the wide diversity of experimental processes involved with DEL technology, keeps track of working protocols in the database, and uses them to command robotic liquid handlers for the synthesis of libraries. This approach provides full traceability of building-blocks and DNA tags in each split-and-pool cycle. Affinity selection experiments and high-throughput sequencing reads are also captured in the database, and the results are automatically deconvoluted and visualized in customizable representations. Researchers can compare results of different experiments and use machine learning methods to discover patterns in data. As of this writing, the platform has been validated through the generation and affinity selection of various libraries, and it has become the cornerstone of the DEL production effort at Lilly. </jats:p>

DNA Encoded Libraries: A Visitor's Guide

“…[82] With regards to larger libraries, improvements in informatic and sequencing technology to rapidly deconvolute hits will have an immediate impact. [82][83][84] Finally, a greater understanding of the dynamics of small molecule binding when attached to DNA could facilitate more effective selections. Ultimately the future success of the DEL-based screening paradigm will be reliant on a community-wide collaboration including both industry and academia to advance technology in informatics, sequencing, biochemistry, and synthetic organic chemistry.…”

“…Despite notable successes, failures still abound in this area stemming from a lack of structural diversity, poorly designed assays, the inability to convert hits to actual leads, and difficulties in rapidly deconvoluting large numbers of false positives from authentic hits . With regards to larger libraries, improvements in informatic and sequencing technology to rapidly deconvolute hits will have an immediate impact . Finally, a greater understanding of the dynamics of small molecule binding when attached to DNA could facilitate more effective selections.…”

Encoded Library Technologies as Integrated Lead Finding Platforms for Drug Discovery

“…First theoretically proposed by Brenner and Lerner in 1992 [4], the selection of LMW compounds from DNA-encoded libraries by now is an established technology employed by numerous academic and industrial laboratories [5,6,7]. Being a scalable benchtop technology for performing affinity-based hit finding, DEL screens facilitate the deep sampling of chemical space by being able to handle very large LMW libraries in a one-pot reaction.…”

A Mild, DNA-Compatible Nitro Reduction Using B2(OH)4

“…DNA-encoded chemical library (DECL) screens are an economic and efficient method for hit discovery. 1 Recent advances in DNA high-throughput sequencing and DNA synthesis have enabled routine screens of large DECL collections, 2 and successful reports of DECL-based target campaigns have spurred wide interest in the platform. 1,3 However, solution-phase synthesis of DECLs is limited by constraints imposed by DNA-integrity and DNA-solubility concerns.…”