Journal
JOURNAL OF MOLECULAR MODELING
Volume 18, Issue 12, Pages 4995-5003Publisher
SPRINGER
DOI: 10.1007/s00894-012-1494-0
Keywords
Drug repositioning; HIV-1 Integrase; Human LEDGF/p75 protein; Molecular docking; Protein-protein interaction
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Funding
- Program for New Century Excellent Talents in University [NCET-08-0774]
- Innovation Program of Shanghai Municipal Education Commission [10ZZ41]
- National Natural Science Foundation of China [90813005, 10979072]
- Specialized Research Fund for the Doctoral Program of Higher Education of China [20090074120012]
- 111 Project [B07023]
- Shanghai Committee of Science and Technology [11DZ2260600]
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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.
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