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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...

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Autores principales: Sutanto, Fandi, Shaabani, Shabnam, Oerlemans, Rick, Eris, Deniz, Patil, Pravin, Hadian, Mojgan, Wang, Meitian, Sharpe, May Elizabeth, Groves, Matthew R., Dömling, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
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.
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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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