Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 Macrodomain of SARS-CoV-2.
Nsp3 macrodomain
coronavirus
fragment-based drug discovery
virtual screening
Journal
bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187
Informations de publication
Date de publication:
28 Jul 2022
28 Jul 2022
Historique:
pubmed:
8
7
2022
medline:
8
7
2022
entrez:
7
7
2022
Statut:
epublish
Résumé
The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with
Identifiants
pubmed: 35794891
doi: 10.1101/2022.06.27.497816
pmc: PMC9258288
pii:
doi:
Types de publication
Preprint
Langues
eng
Commentaires et corrections
Type : UpdateIn
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