In Silico Drug Repurposing for Dermatological Disorders

Resumen

Drug repurposing offers a cost-effective and time-efficient strategy for identifying new uses for existing compounds. This thesis explores a computational drug repurposing pipeline focused on targeting adhesion G protein-coupled receptor E2, a receptor implicated in the rare disease vibratory urticaria and in the pathology of acute myeloid leukemia. Leveraging computational tools for structure prediction, the study models both wild-type and p.C492Y-mutated adhesion G protein-coupled receptor E2 to assess structural alterations that impact ligand accessibility and receptor dissociation. This project explores an in silico pipeline for identifying and characterizing drug repurposing candidates, specifically for dermatological conditions.

Candidate drugs were initially selected based on amino acid association patterns from proteins within the DISNET framework. These were expanded and refined through cheminformatics similarity searches, docking studies using CB-Dock 2, and pathway relevance analysis. Statistical comparisons of binding pocket characteristics between wild-type and mutant forms of adhesion G protein-coupled receptor E2 were also conducted. Binding simulations and drug pathway analyses identified pioglitazone as a potentially impactful agent on adhesion G protein-coupled receptor E2 activity via Peroxisome Proliferator-Activated Receptor gamma mediated suppression of Nuclear Factor kappa-light-chain-enhancer of activated B cells signaling, which downregulates adhesion G protein-coupled receptor E2 transcription and reduces mast cell activation in inflammatory contexts.