Structure-guided optimization of small molecules inhibiting human immunodeficiency virus 1 Tat association with the human coactivator p300/CREB binding protein-associated factor.
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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DOI：
10.1021/jm070014g
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发表时间：
2007-04
影响因子：
7.3
通讯作者：
Chongfeng Pan;M. Mezei;S. Mujtaba;M. Muller,;L. Zeng;Jiaming Li;Zhiyong Wang;Ming-Ming Zhou-Ming
中科院分区：
文献类型：
--
作者：
Chongfeng Pan;M. Mezei;S. Mujtaba;M. Muller,;L. Zeng;Jiaming Li;Zhiyong Wang;Ming-Ming Zhou-Ming
人类免疫缺陷病毒1（HIV-1）反式激活因子达特募集人类转录辅激活因子PCAF（p300/CREB结合蛋白相关因子）以促进整合的HIV-1前病毒的转录。我们在这里报告的小分子抑制剂，选择性地阻止达特和PCAF协会在细胞中的结构为基础的铅优化。我们的铅优化是由受体/铅复合物的巨正则系综模拟指导的，该复合物通过置换配体-受体界面处的弱结合水分子而导致具有改善的铅亲和力的化学修饰的定义。
Human immunodeficiency virus 1 (HIV-1) trans-activator Tat recruits the human transcriptional coactivator PCAF (p300/CREB binding protein-associated factor) to facilitate transcription of the integrated HIV-1 provirus. We report here structure-based lead optimization of small-molecule inhibitors that block selectively Tat and PCAF association in cells. Our lead optimization was guided by grand-canonical ensemble simulation of the receptor/lead complex that leads to definition of chemical modifications with improved lead affinity through displacing weakly bound water molecules at the ligand-receptor interface.