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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle Proteins / chemistry*
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Cell Cycle Proteins / metabolism
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Gene Products, tat / chemistry*
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Gene Products, tat / genetics
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Gene Products, tat / metabolism
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Genes, Reporter
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HIV Long Terminal Repeat
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HIV-1 / genetics
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HIV-1 / metabolism*
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Histone Acetyltransferases / chemistry*
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Histone Acetyltransferases / metabolism
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Humans
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Ligands
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Luciferases / genetics
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Luciferases / metabolism
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Models, Molecular*
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Monte Carlo Method
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Promoter Regions, Genetic
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Propylamines / chemistry*
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Propylamines / pharmacology
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Protein Structure, Tertiary
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Transcription Factors / chemistry*
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Transcription Factors / metabolism
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Transcription, Genetic
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Water / chemistry
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p300-CBP Transcription Factors
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tat Gene Products, Human Immunodeficiency Virus
Substances
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Cell Cycle Proteins
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Gene Products, tat
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Ligands
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Propylamines
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Transcription Factors
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tat Gene Products, Human Immunodeficiency Virus
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Water
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Luciferases
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Histone Acetyltransferases
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p300-CBP Transcription Factors
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p300-CBP-associated factor