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

Fandi Sutanto, Shabnam Shaabani, Rick Oerlemans, Deniz Eris, Pravin Patil, Mojgan Hadian, Meitian Wang, May Elizabeth Sharpe, Matthew R. Groves, Alexander Dömling*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)18231-18239
Number of pages9
JournalAngewandte Chemie (International ed. in English)
Volume60
Issue number33
Early online date7-Jun-2021
DOIs
Publication statusPublished - 9-Aug-2021

Keywords

  • covalent inhibitors
  • high-throughput protein crystallography
  • multicomponent reactions
  • nanosynthesis
  • SARS-CoV-2

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