1161027-08-2Relevant articles and documents
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
Ghosh, Arun K.,Leshchenko-Yashchuk, Sofiya,Anderson, David D.,Baldridge, Abigail,Noetzel, Marcus,Miller, Heather B.,Tie, Yunfeng,Wang, Yuan-Fang,Koh, Yasuhiro,Weber, Irene T.,Mitsuya, Hiroaki
experimental part, p. 3902 - 3914 (2010/01/06)
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.
