Design of HIV-1 Protease Inhibitors with Pyrrolidinones and Oxazolidinones as Novel P1′-Ligands To Enhance Backbone-Binding Interactions with Protease: Synthesis, Biological Evaluation, and Protein−Ligand X-ray Studies
| Autor: | Yunfeng Tie, Hiroaki Mitsuya, Abigail Baldridge, Irene T. Weber, Marcus W. Noetzel, Yuan-Fang Wang, Heather B. Miller, Sofiya Leshchenko-Yashchuk, David D. Anderson, Arun K. Ghosh, Yasuhiro Koh |
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| Rok vydání: | 2009 |
| Předmět: |
Stereochemistry
medicine.medical_treatment Crystallography X-Ray Ligands Article Structure-Activity Relationship HIV-1 protease Drug Discovery medicine Structure–activity relationship HIV Protease Inhibitor Binding site Oxazolidinones Darunavir Binding Sites Protease biology Chemistry HIV Protease Inhibitors Pyrrolidinones Protease inhibitor (biology) Drug Design biology.protein Molecular Medicine Protein Binding medicine.drug Protein ligand |
| Zdroj: | Journal of Medicinal Chemistry. 52:3902-3914 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm900303m |
| Popis: | Structure-based design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors are described. In an effort to enhance interactions with protease backbone atoms, we have incorporated stereochemically defined methyl-2-pyrrolidinone and methyl oxazolidinone as the P1'-ligands. These ligands are designed to interact with Gly-27' carbonyl and Arg-8 side chain in the S1'-subsite of the HIV protease. We have investigated the potential of these ligands in combination with our previously developed bis-tetrahydrofuran (bis-THF) and cyclopentanyltetrahydrofuran (Cp-THF) as the P2-ligands. Inhibitor 19b with a (R)-aminomethyl-2-pyrrolidinone and a Cp-THF was shown to be the most potent compound. This inhibitor maintained near full potency against multi-PI-resistant clinical HIV-1 variants. A high resolution protein-ligand X-ray crystal structure of 19b-bound HIV-1 protease revealed that the P1'-pyrrolidinone heterocycle and the P2-Cp-ligand are involved in several critical interactions with the backbone atoms in the S1' and S2 subsites of HIV-1 protease. |
| Databáze: | OpenAIRE |
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