title: Identification of novel small-molecule inducers of fetal hemoglobin using pharmacophore and 'PSEUDO' receptor models.
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.
authors.affiliation: Boston De Novo Design, 50 Commonwealth Ave, Boston, MA 02116, USA. regine@bostondenovo.com
authors.forename: Regine
authors.initials: R
authors.lastname: Bohacek
authors.forename: Michael S
authors.initials: MS
authors.lastname: Boosalis
authors.forename: Colin
authors.initials: C
authors.lastname: McMartin
authors.forename: Douglas V
authors.initials: DV
authors.lastname: Faller
authors.forename: Susan P
authors.initials: SP
authors.lastname: Perrine
mesh_terms: D000818:Animals; D001665:Binding Sites; D002087:Butyrates / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D005227:Fatty Acids / Q000494:pharmacology*; D005319:Fetal Hemoglobin / Q000235:genetics*; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism; D008156:Luciferases; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology; D015533:Transcriptional Activation
chemical_list: D002087:Butyrates; D005227:Fatty Acids; D010654:Phenylbutyrates; D005319:Fetal Hemoglobin; D008156:Luciferases