Document Report Card

ID: ALA1139870

Journal: J Med Chem

Title: Structure-guided optimization of small molecules inhibiting human immunodeficiency virus 1 Tat association with the human coactivator p300/CREB binding protein-associated factor.

Authors: Pan C, Mezei M, Mujtaba S, Muller M, Zeng L, Li J, Wang Z, Zhou MM.

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.

CiteXplore: 17444627

DOI: 10.1021/jm070014g