Combining High-Throughput Synthesis and High-Throughput Protein Crystallography for Accelerated Hit Identification.
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.
Keywords
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
Similar
MEDLINE
...
LILACS
LIS