7gs4

Publication Abstract from PubMed

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.

Fragment-based screening targeting an open form of the SARS-CoV-2 main protease binding pocket.,Huang CY, Metz A, Lange R, Artico N, Potot C, Hazemann J, Muller M, Dos Santos M, Chambovey A, Ritz D, Eris D, Meyer S, Bourquin G, Sharpe M, Mac Sweeney A Acta Crystallogr D Struct Biol. 2024 Feb 1;80(Pt 2):123-136. doi: , 10.1107/S2059798324000329. Epub 2024 Jan 30. PMID:38289714^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.