Fragment-based screening targeting an open form of the SARS-CoV-2 main protease binding pocket.
Acta Crystallogr D Struct Biol
; 80(Pt 2): 123-136, 2024 Feb 01.
Article
in En
| MEDLINE
| ID: mdl-38289714
ABSTRACT
To identify starting points for therapeutics targeting SARS-CoV-2, the Paul Scherrer Institute and Idorsia decided to collaboratively perform an X-ray crystallographic fragment screen against its main protease. Fragment-based screening was carried out using crystals with a pronounced open conformation of the substrate-binding pocket. Of 631 soaked fragments, a total of 29 hits bound either in the active site (24 hits), a remote binding pocket (three hits) or at crystal-packing interfaces (two hits). Notably, two fragments with a pose that was sterically incompatible with a more occluded crystal form were identified. Two isatin-based electrophilic fragments bound covalently to the catalytic cysteine residue. The structures also revealed a surprisingly strong influence of the crystal form on the binding pose of three published fragments used as positive controls, with implications for fragment screening by crystallography.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
SARS-CoV-2
/
COVID-19
Type of study:
Diagnostic_studies
/
Screening_studies
Limits:
Humans
Language:
En
Journal:
Acta Crystallogr D Struct Biol
/
Acta crystallographica
Year:
2024
Type:
Article
Affiliation country:
Switzerland