"Design and Computational Evaluation of a ROS-Responsive Nintedanib Prodrug for Targeted Treatment of Pulmonary Fibrosis"

Pulmonary fibrosis is a progressive and life-threatening lung disease characterized by excessive extracellular matrix deposition, chronic inflammation, and irreversible remodeling of lung tissue. Oxidative stress and elevated levels of reactive oxygen species (ROS) play central roles in the initiation and progression of pulmonary fibrosis. Although Nintedanib, a multi-target tyrosine kinase inhibitor, has been approved for the treatment of idiopathic pulmonary fibrosis (IPF), its clinical efficacy is limited by gastrointestinal adverse effects, low tissue selectivity, and the need for prolonged administration. The present proposal aims to design and computationally evaluate a novel ROS-responsive prodrug of Nintedanib capable of selectively releasing the active drug in oxidative environments characteristic of fibrotic lung tissue. The proposed prodrug will incorporate a ROS-sensitive linker, such as a thioketal or boronic ester moiety, between Nintedanib and a carrier group to achieve targeted activation within diseased tissues. Computational approaches, including molecular modeling, molecular docking, molecular dynamics (MD) simulations, free-energy calculations, and ADMET predictions, will be employed to investigate the physicochemical properties, stability, and therapeutic potential of the designed prodrug. The study seeks to provide a rational framework for developing targeted therapies that improve efficacy while minimizing systemic toxicity in pulmonary fibrosis.