Fragment-based screening targeting an open form of the SARS-CoV-2 main protease binding pocket

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.

Source: Acta Crystallographica Section D - January 30, 2024 Category: Biochemistry Authors: Huang, C.-Y. Metz, A. Lange, R. Artico, N. Potot, C. Hazemann, J. M ü ller, M. Dos Santos, M. Chambovey, A. Ritz, D. Eris, D. Meyer, S. Bourquin, G. Sharpe, M. Mac Sweeney, A. Tags: 3CLpro SARS-CoV-2 fragment screening covalent binders surface plasmon resonance X-ray crystallography research papers Source Type: research