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.

Graphical abstractLipid-like compounds have been explored for their potential to inhibit mast cell activation and degranulation. Shown is the head group of a new inhibitor of mast cell activation (red) identified by computational extrapolation from the alkylphospholipid chemotype represented by miltefosine (black).Figure optionsDownload full-size imageDownload as PowerPoint slide