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Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function
- Publication Year :
- 2015
-
Abstract
- Small-molecule mimetics of the β-hairpin flap of HIV-1 protease (HIV-1 PR) were designed based on a 1,4-benzodiazepine scaffold as a strategy to interfere with the flap-flap protein-protein interaction, which functions as a gated mechanism to control access to the active site. Michaelis-Menten kinetics suggested our small-molecules are competitive inhibitors, which indicates the mode of inhibition is through binding the active site or sterically blocking access to the active site and preventing flap closure, as designed. More generally, a new bioactive scaffold for HIV-1PR inhibition has been discovered, with the most potent compound inhibiting the protease with a modest K(i) of 11 μM.
- Subjects :
- Stereochemistry
Cell Survival
medicine.medical_treatment
Clinical Biochemistry
Pharmaceutical Science
Plasma protein binding
Virus Replication
Biochemistry
Article
Protein Structure, Secondary
Protein–protein interaction
law.invention
Small Molecule Libraries
Benzodiazepines
Inhibitory Concentration 50
Structure-Activity Relationship
HIV-1 protease
HIV Protease
law
Catalytic Domain
Drug Discovery
medicine
HIV Protease Inhibitor
Structure–activity relationship
Humans
Molecular Biology
Protease
biology
Chemistry
Organic Chemistry
Active site
HIV Protease Inhibitors
Recombinant Proteins
Kinetics
Drug Design
biology.protein
Recombinant DNA
HIV-1
Molecular Medicine
Protein Binding
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....1bf8e7a5263b608d473594ead1aa22ae