Structure-guided optimization of small molecules inhibiting human immunodeficiency virus 1 Tat association with the human coactivator p300/CREB binding protein-associated factor.
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.
Pan
Chongfeng
C
Mezei
Mihaly
M
Mujtaba
Shiraz
S
Muller
Michaela
M
Zeng
Lei
L
Li
Jiaming
J
Wang
Zhiyong
Z
Zhou
Ming-Ming
MM
D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D015696:Gene Products, tat / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009010:Monte Carlo Method; D011401:Promoter Regions, Genetic; D011437:Propylamines / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D014158:Transcription, Genetic; D014867:Water / Q000737:chemistry; D050880:p300-CBP Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D000099224:p300-CBP-Associated Factor
D018797:Cell Cycle Proteins; D015696:Gene Products, tat; D051548:Histone Acetyltransferases; D008024:Ligands; D008156:Luciferases; D011437:Propylamines; D014157:Transcription Factors; D014867:Water; D050880:p300-CBP Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D000099224:p300-CBP-Associated Factor