Computational screening for membrane-directed inhibitors of mast cell activation.
Receptor-mediated signaling events frequently depend on the integrity of their membrane environments. Only a limited number of compounds are currently available that are known or thought to modulate membrane environments and affect signaling events without disrupting membrane structure. Among these are alkylphospholipids including the drug miltefosine that is approved for the treatment of breast cancer and leishmaniasis. In addition, miltefosine has recently been shown to block immunoglobulin E receptor-dependent mast cell activation. On the basis of these findings, we have explored other alkylphospholipids as potential inhibitors of mast cell activation and confirmed the inhibitory activity of five molecules. By comparing the head groups of these alkylphospolipids common pharmacophore features were determined. Through computational screening utilizing this pharmacophore information a new lipid-like inhibitory chemotype was identified that blocked mast cell activation with potency comparable to miltefosine.
Department of Life Science Informatics, B-IT, LIMES, Program Unit Medicinal Chemistry and Chemical Biology, Rheinische Friedrich-Wilhelms-Universität Bonn, Dahlmannstr. 2, D-53113 Bonn, Germany.
José
J
Batista
Tim
T
Friedrichson
Georg
G
Schlechtingen
Tobias
T
Braxmeier
Gary
G
Jennings
Jürgen
J
Bajorath
D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D019295:Computational Biology; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects*; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats