Abstract |
Pharmacologic reinduction of the developmentally silenced fetal ( gamma) globin genes has been achieved in hemoglobinopathy patients using short chain fatty acid derivatives, with therapeutic effects. However, higher-potency inducers than are available in currently identified short chain fatty acid derivatives are desirable for long-term use. Using several short-chain fatty acids with established gamma-globin induction activity, a pharmacophore template was constructed with the TFIT module of the flo software and used to select several new candidate compounds, three of which exhibited significant activity in a gamma-globin gene reporter transcriptional assay which detects only strong inducers. The data were used to construct a new pharmacophore and a 'pseudo' receptor around it. Six hundred and thirty low-molecular weight compounds were docked into this receptor model. Of 26 compounds selected and tested in functional assays, two compounds showed activity >500% over control levels and two had activity 200% over control range, significantly more active than previously identified short chain fatty acid derivative fetal globin gene inducers. Three compounds had less activity; the remainder showed moderate activity. These findings demonstrate the feasibility of using iterative construction of pharmacophores, pseudo-binding site modeling, and virtual screening to identify small molecules with the ability to induce transcription of specific target genes, for potential therapeutics.
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Authors | Regine Bohacek, Michael S Boosalis, Colin McMartin, Douglas V Faller, Susan P Perrine |
Journal | Chemical biology & drug design
(Chem Biol Drug Des)
Vol. 67
Issue 5
Pg. 318-28
(May 2006)
ISSN: 1747-0277 [Print] England |
PMID | 16784456
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Butyrates
- Fatty Acids
- Phenylbutyrates
- Fetal Hemoglobin
- Luciferases
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Topics |
- Animals
- Binding Sites
- Butyrates
(chemistry, pharmacology)
- Cell Line, Tumor
- Drug Design
- Fatty Acids
(pharmacology)
- Fetal Hemoglobin
(genetics)
- Leukemia, Erythroblastic, Acute
(metabolism)
- Luciferases
- Mice
- Models, Molecular
- Molecular Structure
- Phenylbutyrates
(chemistry, pharmacology)
- Transcriptional Activation
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