@article{faa9e91c97b441e993be5188739d7354,
title = "Combining High-Throughput Synthesis and High-Throughput Protein Crystallography for Accelerated Hit Identification",
abstract = "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.",
keywords = "covalent inhibitors, high-throughput protein crystallography, multicomponent reactions, nanosynthesis, SARS-CoV-2",
author = "Fandi Sutanto and Shabnam Shaabani and Rick Oerlemans and Deniz Eris and Pravin Patil and Mojgan Hadian and Meitian Wang and Sharpe, {May Elizabeth} and Groves, {Matthew R.} and Alexander D{\"o}mling",
note = "Funding Information: This research has been supported to (AD) by the National Institute of Health (NIH) (2R01GM097082-05), the European Lead Factory (IMI) under grant agreement number 115489, the Qatar National Research Foundation (NPRP6-065-3-012). Moreover, funding was received through ITN ?Accelerated Early stage drug dIScovery? (AEGIS, grant agreement No 675555) and COFUND ALERT (grant agreement No 665250). Shabnam Shaabani was supported by a KWF Kankerbestrijding grant (grant agreement No 10504). Fandi Sutanto acknowledges Indonesian Endowment Fund for Education (Lembaga Pengelola Dana Pendidikan) for financial support. Deniz Eris is supported by the National Research Programme Covid-19 (NRP78) from the Swiss National Science Foundation (grant number 4078P0_198290). We acknowledge the Paul Scherrer Institut, Villigen, Switzerland for provision of synchrotron radiation beamtime at X06SA, X06DA, and X10S beamlines of the SLS and would like to thank Justyna Wojdyla and Eric Plichta for assistance. We thank Silvia Mansueto, for helping with the purification of some compounds. We acknowledge academical licenses of the Instant Jchem and Scorpion software. We acknowledge Dispensix for borrowing us an I-DOT instrument. Funding Information: This research has been supported to (AD) by the National Institute of Health (NIH) (2R01GM097082‐05), the European Lead Factory (IMI) under grant agreement number 115489, the Qatar National Research Foundation (NPRP6‐065‐3‐012). Moreover, funding was received through ITN “Accelerated Early stage drug dIScovery” (AEGIS, grant agreement No 675555) and COFUND ALERT (grant agreement No 665250). Shabnam Shaabani was supported by a KWF Kankerbestrijding grant (grant agreement No 10504). Fandi Sutanto acknowledges Indonesian Endowment Fund for Education (Lembaga Pengelola Dana Pendidikan) for financial support. Deniz Eris is supported by the National Research Programme Covid‐19 (NRP78) from the Swiss National Science Foundation (grant number 4078P0_198290). We acknowledge the Paul Scherrer Institut, Villigen, Switzerland for provision of synchrotron radiation beamtime at X06SA, X06DA, and X10S beamlines of the SLS and would like to thank Justyna Wojdyla and Eric Plichta for assistance. We thank Silvia Mansueto, for helping with the purification of some compounds. We acknowledge academical licenses of the Instant Jchem and Scorpion software. We acknowledge Dispensix for borrowing us an I‐DOT instrument. Publisher Copyright: {\textcopyright} 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH",
year = "2021",
month = aug,
day = "9",
doi = "10.1002/anie.202105584",
language = "English",
volume = "60",
pages = "18231--18239",
journal = "Angewandte Chemie - International Edition",
issn = "1433-7851",
publisher = "WILEY-V C H VERLAG GMBH",
number = "33",
}