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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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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. |
format | Online Article Text |
id | pubmed-10510511 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
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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