Design of HIV-1 Protease Inhibitors with C3-Substituted Hexahydrocyclopentafuranyl Urethanes as P2-Ligands: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Crystal Structure
| Autor: | Melinda Steffey, Johnson Agniswamy, Masayuki Amano, Garth L. Parham, Hiroaki Mitsuya, Arun K. Ghosh, Irene T. Weber, Yuan-Fang Wang, Bruno D. Chapsal |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Stereochemistry medicine.medical_treatment Crystallography X-Ray Ligands Urethane Article Cell Line Structure-Activity Relationship chemistry.chemical_compound HIV Protease HIV-1 protease Amide Drug Discovery medicine Humans HIV Protease Inhibitor Structure–activity relationship Binding site chemistry.chemical_classification Binding Sites Protease Dose-Response Relationship Drug Molecular Structure biology HIV Protease Inhibitors Protein Structure Tertiary Enzyme Amino Acid Substitution Models Chemical chemistry Drug Design Mutation Biocatalysis HIV-1 biology.protein Molecular Medicine Protein Binding Protein ligand |
| Zdroj: | Journal of Medicinal Chemistry. 54:5890-5901 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm200649p |
| Popis: | We report the design, synthesis, biological evaluation, and the X-ray crystal structure of a novel inhibitor bound to the HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed to interact with the flap Gly48 carbonyl or amide NH in the S2-subsite of the HIV-1 protease. We investigated the potential of those functionalized ligands in combination with hydroxyethylsulfonamide isosteres. Inhibitor 26 containing a 3-(R)-hydroxyl group on the Cp-THF core displayed the most potent enzyme inhibitory and antiviral activity. Our studies revealed a preference for the 3-(R)-configuration over the corresponding 3-(S)-derivative. Inhibitor 26 exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray structure of 26-bound HIV-1 protease revealed important molecular insight into the ligand-binding site interactions. |
| Databáze: | OpenAIRE |
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