Targeting TFF3 in obstructive airway diseases: a computational approach to novel therapeutics

Abstract Background Airway remodeling, a hallmark of chronic obstructive pulmonary disease (COPD) and Mustard lung disease, is influenced by the Trefoil Factor 3 (TFF3). This study sought to pinpoint a compound with minimal toxicity that can effectively suppress TFF3 expression and activity. Methods and Results We employed an integrative approach, combining gene expression analysis, molecular docking, and molecular dynamics simulations, to identify potential TFF3 inhibitors. The biological safety of these compounds was ascertained using a sophisticated deep neural network model. Of the compounds assessed, eight manifested a significant reduction in TFF3 expression, with binding affinities (ΔG) ranging from − 7 to -9.4 kcal/mol. Notably, Genistein emerged as the frontrunner, showcasing potent TFF3 downregulation, minimal toxicity, and a robust inhibitory profile as evidenced by molecular dynamics simulations. Conclusion Genistein holds promise as a therapeutic agent for TFF3-mediated conditions, including mustard lung disease. Its potential to address the current therapeutic gaps is evident, but its clinical utility necessitates further in vitro and in vivo validation.