title: Design and synthesis of potent HIV-1 protease inhibitors incorporating hydroxyprolinamides as novel P2 ligands.
abstract: A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different hydroxyprolinamide P2 ligands were designed and synthesized. Variation of substitutions at the P2 significantly affected the enzyme inhibitory potency of the inhibitors. Compounds 2a and 2d showed excellent enzyme inhibitory activity with IC(50) values in the nanomolar range. An active site binding model for inhibitors 2a and 2d was suggested based upon the computational-docking results of the ligand with HIV-1 protease. This model offers molecular insights regarding ligand-binding site interactions of the hydroxyprolinamide-derived novel P2-ligand.
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong Province, PR China.
authors.forename: Bing-Lei
authors.initials: BL
authors.lastname: Gao
authors.forename: Cheng-Mei
authors.initials: CM
authors.lastname: Zhang
authors.forename: Yi-Zhen
authors.initials: YZ
authors.lastname: Yin
authors.forename: Long-Qian
authors.initials: LQ
authors.lastname: Tang
authors.forename: Zhao-Peng
authors.initials: ZP
authors.lastname: Liu
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D000069454:Darunavir; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D006909:Hydroxyproline / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008024:Ligands; D015394:Molecular Structure; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D017320:HIV Protease Inhibitors; D008024:Ligands; D013449:Sulfonamides; D006909:Hydroxyproline; D000069454:Darunavir