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Dose–Response Activity-Based DNA-Encoded Library Screening

[Image: see text] Dose–response, or “conforming” behavior, increases confidence in a screening hit’s authenticity. Here, we demonstrate dose–response solid-phase DNA-encoded library (DEL) screening. Compound dose in microfluidic droplets is modulated via the UV intensity of photocleavage from DEL be...

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Autores principales: Fitzgerald, Patrick R., Cochrane, Wesley G., Paegel, Brian M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10510511/
https://www.ncbi.nlm.nih.gov/pubmed/37736190
http://dx.doi.org/10.1021/acsmedchemlett.3c00159
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author Fitzgerald, Patrick R.
Cochrane, Wesley G.
Paegel, Brian M.
author_facet Fitzgerald, Patrick R.
Cochrane, Wesley G.
Paegel, Brian M.
author_sort Fitzgerald, Patrick R.
collection PubMed
description [Image: see text] Dose–response, or “conforming” behavior, increases confidence in a screening hit’s authenticity. Here, we demonstrate dose–response solid-phase DNA-encoded library (DEL) screening. Compound dose in microfluidic droplets is modulated via the UV intensity of photocleavage from DEL beads. A 55,296-member DEL was screened at different UV intensities against model enzyme drug targets factor Xa (FXa) and autotaxin (ATX). Both screens yielded photochemical dose-dependent hit rates (FXa hit rates of 0.08/0.05% at 100/30% UV exposure; ATX hit rates of 0.24/0.08% at 100/20% UV exposure). FXa hits contained structures reflective of FXa inhibitors and four hits inhibited FXa (IC(50) = 4.2 ± 0.1, 7.4 ± 0.3, 9.0 ± 0.3, and 19 ± 2 μM.) The top ATX hits (two dihydrobenzamidazolones and a tetrahydroisoquinoline) were validated as inhibitors (IC(50) = 7 ± 2, 13 ± 2, and 1 ± 0.3 μM). Photochemical dose–response DEL screening data prioritized hits for synthesis, the rate-limiting step in DEL lead identification.
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spelling pubmed-105105112023-09-21 Dose–Response Activity-Based DNA-Encoded Library Screening Fitzgerald, Patrick R. Cochrane, Wesley G. Paegel, Brian M. ACS Med Chem Lett [Image: see text] Dose–response, or “conforming” behavior, increases confidence in a screening hit’s authenticity. Here, we demonstrate dose–response solid-phase DNA-encoded library (DEL) screening. Compound dose in microfluidic droplets is modulated via the UV intensity of photocleavage from DEL beads. A 55,296-member DEL was screened at different UV intensities against model enzyme drug targets factor Xa (FXa) and autotaxin (ATX). Both screens yielded photochemical dose-dependent hit rates (FXa hit rates of 0.08/0.05% at 100/30% UV exposure; ATX hit rates of 0.24/0.08% at 100/20% UV exposure). FXa hits contained structures reflective of FXa inhibitors and four hits inhibited FXa (IC(50) = 4.2 ± 0.1, 7.4 ± 0.3, 9.0 ± 0.3, and 19 ± 2 μM.) The top ATX hits (two dihydrobenzamidazolones and a tetrahydroisoquinoline) were validated as inhibitors (IC(50) = 7 ± 2, 13 ± 2, and 1 ± 0.3 μM). Photochemical dose–response DEL screening data prioritized hits for synthesis, the rate-limiting step in DEL lead identification. American Chemical Society 2023-08-21 /pmc/articles/PMC10510511/ /pubmed/37736190 http://dx.doi.org/10.1021/acsmedchemlett.3c00159 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Fitzgerald, Patrick R.
Cochrane, Wesley G.
Paegel, Brian M.
Dose–Response Activity-Based DNA-Encoded Library Screening
title Dose–Response Activity-Based DNA-Encoded Library Screening
title_full Dose–Response Activity-Based DNA-Encoded Library Screening
title_fullStr Dose–Response Activity-Based DNA-Encoded Library Screening
title_full_unstemmed Dose–Response Activity-Based DNA-Encoded Library Screening
title_short Dose–Response Activity-Based DNA-Encoded Library Screening
title_sort dose–response activity-based dna-encoded library screening
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10510511/
https://www.ncbi.nlm.nih.gov/pubmed/37736190
http://dx.doi.org/10.1021/acsmedchemlett.3c00159
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