Molecular Modeling Guided Design of Modulators of FcεRIα for the Therapeutic Treatment of Anaphylaxis

Abstract

Anaphylactic shock is a severe, potentially life-threatening, generalized, or systemic type-I hypersensitivity reaction. It triggers severe multi-organ responses such as cardiac, respiratory, and skin. This condition occurs due to the sudden release of inflammatory mediators derived from mast cells and basophils via degranulation. Mast cells and basophils activation due to IgE are the key cause of these responses. This activation releases inflammatory mediators such as histamine, chemokines, and leukotrienes. In past, the best strategy for this disease is symptom management. The second treatment for this disease is epinephrine or antihistamine drugs which are symptomatic treatment drugs. But these drugs cannot be used by cardiac patients, asthmatic patients and children. Antihistamine drugs cannot stop Vasoconstriction. That’s why there is a need for direct treatment of anaphylaxis with low toxicity, high efficacy and site-specific delivery of drugs. With the introduction of novel target “FcєRIα”, involved in this disease by providing linkage between allergen-specific IgE and mast cells, we proposed to target this receptor. Therefore, in this project, a structure-based strategy was opted to explore the binding hypothesis of numerous modulators which can help in the controlled release of inflammatory mediators. The methodology includes identification of targets, and chemical compounds, molecular dynamic simulation, and drug toxicity profiling. FM1 has shown high binding affinity against key residues Trp113, Lys154, Trp156 and Gln157 with IC50(M):0.0003, GOLD score: 40.75, Glide docking: -3.656 kcal/mol, sscore: -6.5436 kcal/mol and MM/GBSA binding energy: -17.31. FM1 also showed structural stability with essential residues of human FcєRIα with ~ 0.9Å change in RMSD. Drug toxicity profiling and compatible binding confirmation with best binding energy scores “FM1” is proposed to be the best candidate among used ligands as a modulator of FcєRIα to control the release of inflammatory mediators to treat anaphylaxis. In our case additional hydrogen bonding is playing key role towards binding potential of used modulators. Epothilone D can be used for drug repurposing while Ajugasterone C, Euscaphic acid, Gravacridondiol and Luteolin as natural source modulators of human FcєRIα