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Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening
- Source :
- Molecules, Volume 24, Issue 14, Molecules, vol. 24, no. 14, 2590, 2019., Molecules, Vol 24, Iss 14, p 2590 (2019)
-
Abstract
- Large-scale virtual screening of boronic acid derivatives was performed to identify nonpeptidic covalent inhibitors of the &beta<br />5i 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.
- Subjects :
- Models, Molecular
inorganic chemicals
Drug Evaluation, Preclinical
Pharmaceutical Science
01 natural sciences
Article
Analytical Chemistry
lcsh:QD241-441
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
immunoproteasome
lcsh:Organic chemistry
udc:615.4:54
Drug Discovery
Computer Simulation
Physical and Theoretical Chemistry
030304 developmental biology
β5i selective inhibitor
0303 health sciences
Virtual screening
Molecular Structure
010405 organic chemistry
Chemistry
Organic Chemistry
virtual screening
Boronic Acids
Combinatorial chemistry
0104 chemical sciences
3. Good health
Molecular Docking Simulation
Inhibitory potency
Chemistry (miscellaneous)
Covalent bond
Docking (molecular)
Molecular Medicine
covalent inhibitor
Proteasome Inhibitors
Boronic acid
Subjects
Details
- Language :
- English
- ISSN :
- 14203049
- Volume :
- 24
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Molecules
- Accession number :
- edsair.doi.dedup.....c7d1b04e37024272fb4be73b07f2e94e
- Full Text :
- https://doi.org/10.3390/molecules24142590