Barcode-free hit discovery from massive libraries enabled by automated small molecule structure annotation
Year: 2024
Type: article
Abstract: Affinity-selection platforms are powerful tools for early drug discovery. Among these, DNA-encoded libraries (DELs) have found widespread application. However, the DNA barcodes required for the decoding of hit-compounds bring challenges in terms of synthesis complexity and reaction scope, and can also influence binding by interacting with the target. We present a self-encoded library (SEL) platform that simultaneously screens a million small molecules without barcoding tags. We developed computational methods to automatically decode each query MS/MS spectrum of a selection outcome, matching it against the molecular structures of the library. We validated our platform in affinity-selections, identifying binders for the oncologic targets CAIX and Exonuclease-1. Screening barcode-free libraries of this scale is unprecedented and promises substantial impact on both academic and industrial early drug discovery.
Authors: van der Nol, Edith, Haupt, Nils Alexander, Gao, Qing Qing, Smit, Benthe A.M., Hoffmann, Martin Andre, Engler-Lukajewski, Martin, Ludwig, Marcus, McKenna, Sean, Mata, J. Miguel, Béquignon, Olivier J. M., van Westen, Gerard, Wendel, Tiemen J., Noordermeer, Sylvie M., Pomplun, Sebastian, Böcker, Sebastian
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6893069145
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