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Discovery of a novel HIV‐1 integrase inhibitor from natural compounds through structure based virtual screening and cell imaging
Author(s) -
Gu Wan-Gang,
Zhang Xuan,
Ip Denis Tsz-Ming,
Yang Liu-Meng,
Zheng Yong-Tang,
Wan David Chi-Cheong
Publication year - 2014
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2014.08.004
Subject(s) - integrase , integrase inhibitor , virtual screening , chemistry , drug discovery , human immunodeficiency virus (hiv) , computational biology , cell , stereochemistry , biochemistry , virology , microbiology and biotechnology , biology , gene , viral load , antiretroviral therapy
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.