Combining High-Throughput Synthesis and High-Throughput Protein Crystallography for Accelerated Hit Identification.

Autor: Sutanto F; University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Shaabani S; University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Oerlemans R; University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Eris D; Photon Science Division, Paul Scherrer Institute, Switzerland., Patil P; University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Hadian M; University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Wang M; Photon Science Division, Paul Scherrer Institute, Switzerland., Sharpe ME; Photon Science Division, Paul Scherrer Institute, Switzerland., Groves MR; University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Dömling A; University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713, AV, Groningen, The Netherlands.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2021 Aug 09; Vol. 60 (33), pp. 18231-18239. Date of Electronic Publication: 2021 Jul 09.
DOI: 10.1002/anie.202105584
Abstrakt: 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.
(© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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