文献类型：期刊文献

英文题名：Identification of old drugs as potential inhibitors of HIV-1 integrase - human LEDGF/p75 interaction via molecular docking

作者：Hu, Guoping[1];Li, Xi[1];Sun, Xianqiang[1];Lu, Weiqiang[1];Liu, Guixia[1];Huang, Jin[1];Shen, Xu[2];Tang, Yun[1]

机构：[1]E China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

年份：2012

卷号：18

期号：12

起止页码：4995

外文期刊名：JOURNAL OF MOLECULAR MODELING

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000311400100004)】；

基金：This work was supported by the Program for New Century Excellent Talents in University (Grant NCET-08-0774), the Innovation Program of Shanghai Municipal Education Commission (Grant 10ZZ41), the National Natural Science Foundation of China (Grants 90813005 and 10979072), the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant 20090074120012), the 111 Project (Grant B07023), and the Shanghai Committee of Science and Technology (Grant 11DZ2260600). We thank the National Compound Resource Center for providing compounds. The cDNA coding for HIV IN catalytic core domain (IN CCD) (residues 50-212) including the F185K solubilizing-mutation was a gift from Prof. Robert Craigie (National Institutes of Health, Bethesda, MD). The full-length plasmid pCPNat p75 was kindly provided by Prof. Zeger Debyser (Katholieke Universiteit Leuven, Belgium).

语种：英文

外文关键词：Drug repositioning; HIV-1 Integrase; Human LEDGF/p75 protein; Molecular docking; Protein-protein interaction

摘要：Integration of viral-DNA into host chromosome mediated by the viral protein HIV-1 integrase (IN) is an essential step in the HIV-1 life cycle. In this process, human protein Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration. LEDGF/p75-HIV-1 IN interaction represents an attractive target for anti-HIV therapy. In this study, approved drugs were investigated for the finding of potential inhibitors on this target. Via molecular docking against the LEDGF/p75-binding pocket of HIV-1 IN, 26 old drugs were selected from the DrugBank and purchased for bioassays. Among them, eight, namely Atorvastatin, Bumetanide, Candesartan, Carbidopa, Diclofenac, Diflunisal, Eprosartan, and Sulindac, were identified as potential inhibitors of LEDGF/p75- HIV-1 IN interaction, whose IC50 values ranged from 6.5 mu M to 36.8 mu M. In addition, Atorvastatin was previously reported to block HIV-1 replication and may have an important implication for the treatment of AIDS. Our results suggested a mechanism of action for the anti-HIV effects of Atorvastatin. This work provides a new example of inhibitors targeting protein-protein interaction and confirmed that old drugs were valuable sources for antiviral drug discovery.