Structure-Guided Optimization of Small Molecules Inhibiting Human Immunodeficiency Virus 1 Tat Association with the Human Coactivator p300/CREB Binding Protein-Associated Factor
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- 作者：Chongfeng Pan ; Mihaly Mezei ; Shiraz Mujtaba ; Michaela Muller ; Lei Zeng ; Jiaming Li ; Zhiyong Wang ; Ming-Ming Zhou
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：May 17, 2007
- 年：2007
- 卷：50
- 期：10
- 页码：2285 - 2288
- 全文大小：169K
- 年卷期：v.50,no.10(May 17, 2007)
- ISSN：1520-4804
文摘
Human immunodeficiency virus 1 (HIV-1) trans-activatorTat recruits the human transcriptional coactivator PCAF (p300/CREBbinding protein-associated factor) to facilitate transcription of theintegrated HIV-1 provirus. We report here structure-based leadoptimization of small-molecule inhibitors that block selectively Tat andPCAF association in cells. Our lead optimization was guided by grand-canonical ensemble simulation of the receptor/lead complex that leadsto definition of chemical modifications with improved lead affinitythrough displacing weakly bound water molecules at the ligand-receptor interface.