title: Discovery of a novel HIV-1 integrase inhibitor from natural compounds through structure based virtual screening and cell imaging.
abstract: The interaction between HIV-1 integrase and LEDGF/P75 has been validated as a target for anti-HIV drug development. Based on the crystal structure of integrase in complex with LEDGF/P75, a library containing 80 thousand natural compounds was filtered with virtual screening. 11 hits were selected for cell based assays. One compound, 3-(1,3-benzothiazol-2-yl)-8-{[bis(2-hydroxyethyl)amino]methyl}-7-hydroxy-2H-chromen-2-one (D719) inhibited integrase nuclear translocation in cell imaging. The binding mode of D719 was analyzed with molecular simulation. The anti-HIV activity of D719 was assayed by measuring the p24 antigen production in acute infection. The structure characteristics of D719 may provide valuable information for integrase inhibitor design.
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Department of Immunology, Zunyi Medical University, Zunyi, China.
authors.forename: Wan-Gang
authors.initials: WG
authors.lastname: Gu
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Denis Tsz-Ming
authors.initials: DT
authors.lastname: Ip
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Liu-Meng
authors.initials: LM
authors.lastname: Yang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Yong-Tang
authors.initials: YT
authors.lastname: Zheng
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region. Electronic address: chicheongwan@cuhk.edu.hk.
authors.forename: David Chi-Cheong
authors.initials: DC
authors.lastname: Wan
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D052160:Benzothiazoles / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D003198:Computer Simulation; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D019427:HIV Integrase / Q000737:chemistry; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding
chemical_list: C000592899:3-(1,3-benzothiazol-2-yl)-8-((bis(2-hydroxyethyl)amino)methyl)-7-hydroxy-2H-chromen-2-one; D052160:Benzothiazoles; D003374:Coumarins; D016655:HIV Core Protein p24; D019428:HIV Integrase Inhibitors; C514799:p24 protein, Human Immunodeficiency Virus Type 1; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: HIV-1 integrase; Lens epithelium-derived growth factor (LEDGF/P75); Virtual screening