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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.
  • 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.
Angew Chem Int Ed Engl ; 60(33): 18231-18239, 2021 08 09.
Article in English | MEDLINE | ID: covidwho-1303235
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Cysteine Proteinase Inhibitors / Small Molecule Libraries / Coronavirus 3C Proteases Language: English Journal: Angew Chem Int Ed Engl Year: 2021 Document Type: Article Affiliation country: Anie.202105584

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Cysteine Proteinase Inhibitors / Small Molecule Libraries / Coronavirus 3C Proteases Language: English Journal: Angew Chem Int Ed Engl Year: 2021 Document Type: Article Affiliation country: Anie.202105584