Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening.
Molecules
; 24(14)2019 Jul 16.
Article
em En
| MEDLINE
| ID: mdl-31315311
ABSTRACT
Large-scale virtual screening of boronic acid derivatives was performed to identify nonpeptidic covalent inhibitors of the ß5i subunit of the immunoproteasome. A hierarchical virtual screening cascade including noncovalent and covalent docking steps was applied to a virtual library of over 104,000 compounds. Then, 32 virtual hits were selected, out of which five were experimentally confirmed. Biophysical and biochemical tests showed micromolar binding affinity and time-dependent inhibitory potency for two compounds. These results validate the computational protocol that allows the screening of large compound collections. One of the lead-like boronic acid derivatives identified as a covalent immunoproteasome inhibitor is a suitable starting point for chemical optimization.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article