title: 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.
abstract: 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.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Sofiya
authors.initials: S
authors.lastname: Leshchenko-Yashchuk
authors.forename: David D
authors.initials: DD
authors.lastname: Anderson
authors.forename: Abigail
authors.initials: A
authors.lastname: Baldridge
authors.forename: Marcus
authors.initials: M
authors.lastname: Noetzel
authors.forename: Heather B
authors.initials: HB
authors.lastname: Miller
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Tie
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Wang
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D023303:Oxazolidinones; D011760:Pyrrolidinones