title: Discovery of inhibitors to block interactions of HIV-1 integrase with human LEDGF/p75 via structure-based virtual screening and bioassays.
abstract: This study aims to identify inhibitors that bind at the interface of HIV-1 integrase (IN) and human LEDGF/p75, which represents a novel target for anti-HIV therapy. To date, only a few such inhibitors have been reported. Here structure-based virtual screening was performed to search for the inhibitors from an in-house library of natural products and their derivatives. Among the 38 compounds selected by our strategy, 18 hits were discovered. The two most potent inhibitors showed IC(50) values at 0.32 and 0.26 μM, respectively. Three compounds were subsequently selected for anti-HIV assays, among which (E)-3-(2-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one (NPD170) showed the highest antiviral activity (EC(50) = 1.81 μM). The antiviral mechanism of these compounds was further explored, and the results validated that the compounds interrupted the binding of transfected IN to endogenous LEDGF/p75. These findings could be helpful for anti-HIV drug discovery.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Hu
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Yaozong
authors.initials: Y
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.forename: Liu-Meng
authors.initials: LM
authors.lastname: Yang
authors.forename: Guixia
authors.initials: G
authors.lastname: Liu
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Lihong
authors.initials: L
authors.lastname: Hu
authors.forename: Yong-Tang
authors.initials: YT
authors.lastname: Zheng
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001681:Biological Assay; D016923:Cell Death / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C577955:3-(2-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one; D048868:Adaptor Proteins, Signal Transducing; D019380:Anti-HIV Agents; D047188:Chalcones; D019428:HIV Integrase Inhibitors; C504649:PSIP1 protein, human; D014157:Transcription Factors; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1