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Highly Potent HIV-1 Protease Inhibitors with Novel Tricyclic P2 Ligands: Design, Synthesis, and Protein–Ligand X-ray Studies
- Source :
- Journal of Medicinal Chemistry. 56:6792-6802
- Publication Year :
- 2013
- Publisher :
- American Chemical Society (ACS), 2013.
-
Abstract
- The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2-ligands are described. Various substituent effects were investigated in order to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity while incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f have maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions which may account for the inhibitor’s potent antiviral activity and excellent resistance profiles.
- Subjects :
- Models, Molecular
Magnetic Resonance Spectroscopy
Stereochemistry
medicine.medical_treatment
Crystallography, X-Ray
Ligands
Article
Mass Spectrometry
Sulfone
chemistry.chemical_compound
HIV Protease
HIV-1 protease
Drug Discovery
medicine
HIV Protease Inhibitor
chemistry.chemical_classification
Protease
biology
Active site
HIV Protease Inhibitors
Multiple drug resistance
Biochemistry
chemistry
biology.protein
Molecular Medicine
Tricyclic
Protein ligand
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....5ecbd2997fed426944805f8fa3f98263