Identification of Novel Small-molecule Inducers of Fetal Hemoglobin Using Pharmacophore and ‘PSEUDO’ Receptor Models

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Abstract

Pharmacologic reinduction of the developmentally silenced fetal (γ) 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 γ-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 γ-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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