Pharmacophore Development Aimed at Inhibiting the Spi-1/DNA: C/EBP

Interaction
Cribas, Emily S.1; Auron, Philip E.2; and Madura, Jeffry D.3
Pennsylvania State University, University Park, PA 168021; Departments of Biological
Sciences2; Chemistry and Biochemistry, Center of Computational Sciences3, Duquesne
University, 600 Forbes Ave., Pittsburgh, PA 15282
The Spi-1/PU.1 and the C/EBP transcription factors cooperate via a critical proteinprotein interaction at the promoter of the human IL1B gene, coding for Interleukin (IL1), a macrophage cytokine that mediates acute inflammatory responses, but can also
lead to chronic disease when highly expressed. IL-1-dependent inflammation may be
prevented through the discovery of a small molecule that can bind to a pocket formed in
the DNA major groove in the vicinity of Arginine 232 in Spi-1/PU.1, a recognition site
for C/EBP interaction. We used MMTSB tools for structure preparation and solvation of
the Spi-1/DNA complex, as well as NAMD 2.9 to conduct molecular dynamics (MD)
simulations in order to generate a stable complex. The stable complex will be used to
generate a pharmacophore that will be used to screen a library of small molecules using
MOE. The results of this project provide a basis for developing an effective antiinflammatory therapeutic.