Design of an Automated Reagent-Dispensing System for Reaction Screening and Validation with DNA-Tagged Substrates

Abstract

Laboratory automation strategies have vast potential for accelerating discovery processes. They enable higher efficiency and throughput for time-consuming screening procedures and reduce error-prone manual steps. Automating repetitive procedures can for instance support chemists in optimizing chemical reactions. Particularly, the technology of DNA-encoded libraries (DELs) may benefit from automation techniques, since translation of chemical reactions to DNA-tagged reactants often requires screening of multiple reaction parameters and evaluation of large numbers of reactants. Here, we describe a portable, automated system for reagent dispensing that was designed from open source materials. The system was validated by performing amide coupling of carboxylic acids to DNA-linked amine and a micelle-mediated Povarov reaction to DNA-tagged hexahydropyrroloquinolines. The latter reaction required accurate pipetting of multiple components including different solvents and a surface-active reagent. Analysis of reactions demonstrated that the robotic system achieved high accuracy comparable to experimentation by an experienced chemist with the potential of higher throughput.

Development of an Automatable Affinity Purification Process for DNA-Encoded Chemistry

“…The ADoS workspace consisted of six flexible positions with the dimensions of a standardized 96-microwell plate (127.76 mm × 85.48 mm). 33 This design used self-made and 3D-printed modules in the same dimensions as the developed vacuum chamber in this work. The modified workspace of the ADoS for washing with a 96-microwell filter plate is shown in Figure 3 D. It consists of a 96-microwell plate with the five washing solvents (aqueous EDTA, DMF, MeOH, MeCN, CH 2 Cl 2 ), the designed vacuum chamber for washing, and a cleaning station for continuous cleaning of the automated injection unit (AIU).…”

Two-Phase Flow in a Coiled Flow Inverter: Process Development from Batch to Continuous Flow

“…For more efficient and effective lab work, pipetting robots from well-known companies are commercially available. Besides these commercial products, open-source and off-the-shelf solutions for lab applications even for reaction screening of DNA-encoded reactions were and are developed. , The open-source concept allows for adapting the lab robot on specific applications such as cleaning processes, purification of products, or analytical purposes and applications. Bobers et al developed an automated reactant-dispensing system based on open-source components as 3D printed parts and micro controllers .…”

“…Besides these commercial products, open-source and off-the-shelf solutions for lab applications even for reaction screening of DNA-encoded reactions were and are developed. , The open-source concept allows for adapting the lab robot on specific applications such as cleaning processes, purification of products, or analytical purposes and applications. Bobers et al developed an automated reactant-dispensing system based on open-source components as 3D printed parts and micro controllers . The workspace of a former 3D printer design was modularized and adapted with regards to the size of six standard 96-well microtiter plates.…”

“…Bobers et al developed an automated reactantdispensing system based on open-source components as 3D printed parts and micro controllers. 31 The workspace of a former 3D printer design was modularized and adapted with regards to the size of six standard 96-well microtiter plates. The accuracy and reproducibility of the robot were tested and validated by performing a multicomponent DNA-tagged Povarov reaction batch-wise with different cosolvents and catalyst concentrations.…”

Recent Advances on the Selection Methods of DNA‐Encoded Libraries

“…Figure 1 lays out the four major technological components of DELs: 1) chemistry, 2) encoding, 3) selection, and 4) hit decoding and data analysis. Recent literatures have offered many comprehensive reviews, highlights, perspectives, and books covering nearly every aspect of DELs as well as its applications [10,14a, 28] . Earlier DEL reviews mostly discussed the encoding methods, i. e. how to efficiently build up large‐scale DELs with high‐precision encoding, while the more recent ones tend to focus on the development of new chemistries for DELs to access more diverse structures, new data analysis methods for more reliable hit deconvolution, automation and industrialization, and practical applications in drug discovery [29] .…”