Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative design
| Autor: | Heather Dawson, Mitchell Lennert J, Kathy K. Lewis, Stephanie Webber, Dominic Andrada, B.‐W. Wu, Krzysztof Appelt, Anthony J. Trippe, Dan K. Gehlhaar, Deborah Kahil, Dzuy T. Nguyen, Jay F. Davies, Bhasker V. Shetty, L. Musick, Reich Siegfried Heinz, Melnick Michael J, Maha Kosa |
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| Rok vydání: | 1996 |
| Předmět: |
Molecular model
medicine.drug_class Stereochemistry medicine.medical_treatment Carboxamide Antiviral Agents Cell Line chemistry.chemical_compound Mice Structure-Activity Relationship Protein structure Dogs HIV-1 protease Amide Drug Discovery medicine Animals Humans chemistry.chemical_classification Protease biology Molecular Structure Chemistry HIV Protease Inhibitors Haplorhini Amides Rats Enzyme Enzyme inhibitor Drug Design biology.protein HIV-1 Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 39(14) |
| ISSN: | 0022-2623 |
| Popis: | A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, bis tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein-ligand complex of 9 revealed the inhibitor binds in an inverted binding mode relative to 3. Examination of the protein-ligand complex of 9 suggested several modifications in the P1 and P1' pockets. Through these modifications it was possible to improve the activity of the inhibitors another 100-fold, highlighting the utility of crystallographic feedback in inhibitor design. These compounds were found to have good antiviral activity in cell culture, were selective for the HIV protease, and were orally available in three animal models. |
| Databáze: | OpenAIRE |
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