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Combining High‐Throughput Synthesis and High‐Throughput Protein Crystallography for Accelerated Hit Identification
Protein crystallography (PX) is widely used to drive advanced stages of drug optimization or to discover medicinal chemistry starting points by fragment soaking. However, recent progress in PX could allow for a more integrated role into early drug discovery. Here, we demonstrate for the first time t...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456925/ https://www.ncbi.nlm.nih.gov/pubmed/34097796 http://dx.doi.org/10.1002/anie.202105584 |
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author | Sutanto, Fandi Shaabani, Shabnam Oerlemans, Rick Eris, Deniz Patil, Pravin Hadian, Mojgan Wang, Meitian Sharpe, May Elizabeth Groves, Matthew R. Dömling, Alexander |
author_facet | Sutanto, Fandi Shaabani, Shabnam Oerlemans, Rick Eris, Deniz Patil, Pravin Hadian, Mojgan Wang, Meitian Sharpe, May Elizabeth Groves, Matthew R. Dömling, Alexander |
author_sort | Sutanto, Fandi |
collection | PubMed |
description | Protein crystallography (PX) is widely used to drive advanced stages of drug optimization or to discover medicinal chemistry starting points by fragment soaking. However, recent progress in PX could allow for a more integrated role into early drug discovery. Here, we demonstrate for the first time the interplay of high throughput synthesis and high throughput PX. We describe a practical multicomponent reaction approach to acrylamides and ‐esters from diverse building blocks suitable for mmol scale synthesis on 96‐well format and on a high‐throughput nanoscale format in a highly automated fashion. High‐throughput PX of our libraries efficiently yielded potent covalent inhibitors of the main protease of the COVID‐19 causing agent, SARS‐CoV‐2. Our results demonstrate, that the marriage of in situ HT synthesis of (covalent) libraires and HT PX has the potential to accelerate hit finding and to provide meaningful strategies for medicinal chemistry projects. |
format | Online Article Text |
id | pubmed-8456925 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84569252021-09-27 Combining High‐Throughput Synthesis and High‐Throughput Protein Crystallography for Accelerated Hit Identification Sutanto, Fandi Shaabani, Shabnam Oerlemans, Rick Eris, Deniz Patil, Pravin Hadian, Mojgan Wang, Meitian Sharpe, May Elizabeth Groves, Matthew R. Dömling, Alexander Angew Chem Int Ed Engl Research Articles Protein crystallography (PX) is widely used to drive advanced stages of drug optimization or to discover medicinal chemistry starting points by fragment soaking. However, recent progress in PX could allow for a more integrated role into early drug discovery. Here, we demonstrate for the first time the interplay of high throughput synthesis and high throughput PX. We describe a practical multicomponent reaction approach to acrylamides and ‐esters from diverse building blocks suitable for mmol scale synthesis on 96‐well format and on a high‐throughput nanoscale format in a highly automated fashion. High‐throughput PX of our libraries efficiently yielded potent covalent inhibitors of the main protease of the COVID‐19 causing agent, SARS‐CoV‐2. Our results demonstrate, that the marriage of in situ HT synthesis of (covalent) libraires and HT PX has the potential to accelerate hit finding and to provide meaningful strategies for medicinal chemistry projects. John Wiley and Sons Inc. 2021-07-09 2021-08-09 /pmc/articles/PMC8456925/ /pubmed/34097796 http://dx.doi.org/10.1002/anie.202105584 Text en © 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Sutanto, Fandi Shaabani, Shabnam Oerlemans, Rick Eris, Deniz Patil, Pravin Hadian, Mojgan Wang, Meitian Sharpe, May Elizabeth Groves, Matthew R. Dömling, Alexander Combining High‐Throughput Synthesis and High‐Throughput Protein Crystallography for Accelerated Hit Identification |
title | Combining High‐Throughput Synthesis and High‐Throughput Protein Crystallography for Accelerated Hit Identification |
title_full | Combining High‐Throughput Synthesis and High‐Throughput Protein Crystallography for Accelerated Hit Identification |
title_fullStr | Combining High‐Throughput Synthesis and High‐Throughput Protein Crystallography for Accelerated Hit Identification |
title_full_unstemmed | Combining High‐Throughput Synthesis and High‐Throughput Protein Crystallography for Accelerated Hit Identification |
title_short | Combining High‐Throughput Synthesis and High‐Throughput Protein Crystallography for Accelerated Hit Identification |
title_sort | combining high‐throughput synthesis and high‐throughput protein crystallography for accelerated hit identification |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456925/ https://www.ncbi.nlm.nih.gov/pubmed/34097796 http://dx.doi.org/10.1002/anie.202105584 |
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