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Combining High‐Throughput Synthesis and High‐Throughput Protein Crystallography for Accelerated Hit Identification
Author(s) -
Sutanto Fandi,
Shaabani Shabnam,
Oerlemans Rick,
Eris Deniz,
Patil Pravin,
Hadian Mojgan,
Wang Meitian,
Sharpe May Elizabeth,
Groves Matthew R.,
Dömling Alexander
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202105584
Subject(s) - throughput , drug discovery , covalent bond , identification (biology) , fragment (logic) , computer science , combinatorial chemistry , nanotechnology , computational biology , high throughput screening , nanoscopic scale , chemistry , materials science , biology , biochemistry , organic chemistry , algorithm , telecommunications , botany , wireless
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.