COMPUTATIONAL SCREENING FOR NOVEL INHIBITORS OF PROTEINS IN THE MAST CELL DEGRANULATION PATHWAY

Abstract

Allergies are a pervasive issue and require novel ways of alleviating symptoms. Existing treatments focus on symptom management and immunotherapy in response to an allergic reaction. However, there is also the potential for prophylactic treatment that inhibits molecules involved in the mast cell degranulation pathway, which causes allergic symptoms. We identified potential target proteins downstream of this pathway including PKC, PLCγ, and PI3K isoforms, the activation of which results in the degranulation of mast cells. We computationally modeled protein-inhibitor binding interactions and identified inhibitors with the predicted highest binding affinity to the target pathway proteins. For the most efficient inhibitors, we extended our analysis by construction of analogs to determine which chemical properties of the inhibitors contributed to the highest binding affinity. The identified possible inhibitors have the potential to hinder mast cell degranulation, limit histamine and cytokine release, and therefore prevent allergic symptoms, making them ideal targets for future pharmacology research.