PMID:17444627
| Citation |
Pan, C, Mezei, M, Mujtaba, S, Muller, M, Zeng, L, Li, J, Wang, Z and Zhou, MM (2007) Structure-guided optimization of small molecules inhibiting human immunodeficiency virus 1 Tat association with the human coactivator p300/CREB binding protein-associated factor. J. Med. Chem. 50:2285-8 |
|---|---|
| Abstract |
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. |
| Links |
PubMed Online version:10.1021/jm070014g |
| Keywords |
Cell Cycle Proteins/chemistry; Cell Cycle Proteins/metabolism; Gene Products, tat/chemistry; Gene Products, tat/genetics; Gene Products, tat/metabolism; Genes, Reporter; HIV Long Terminal Repeat; HIV-1/genetics; HIV-1/metabolism; Histone Acetyltransferases/chemistry; Histone Acetyltransferases/metabolism; Humans; Ligands; Luciferases/genetics; Luciferases/metabolism; Models, Molecular; Monte Carlo Method; Promoter Regions, Genetic; Propylamines/chemistry; Propylamines/pharmacology; Protein Structure, Tertiary; Transcription Factors/chemistry; Transcription Factors/metabolism; Transcription, Genetic; Water/chemistry; p300-CBP Transcription Factors; tat Gene Products, Human Immunodeficiency Virus |
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