This study investigates the drug delivery mechanism into the distal lung airways utilizing an in-silico approach. Dexamethasone is a steroidal anti-inflammatory drug under investigation for its effectiveness in treating inflammation via pulmonary delivery. For these drugs to function optimally, their adsorption by lung surfactants a monolayer at the air-water interface in alveoli that reduces surface tension is essential. Understanding the molecular interactions between dexamethasone and lung surfactants is critical to elucidating this adsorption process. This study employs coarse-grained molecular dynamics simulations to explore the concentration-dependent impact of dexamethasone on a lung surfactant monolayer (LSM) composed of lipids under two breathing states: exhalation (surface tension 0 ) and inhalation (surface tension 20–25 ). Simulations using fixed-area-per-lipid (APL) and fixed-surface-tension methods confirm that the model LSM effectively replicates surface tension dynamics and compressibility across compressed and expanded states without dexamethasone. Analysis of three dexamethasone concentrations reveals that the drug influences the structure and dynamics of the LSM in a concentration-dependent fashion, leading to monolayer collapse mediated by surfactant proteins and surface tension. Through computational modeling and simulation, we explore the behavior of various drug formulations and delivery systems within the complex anatomical structures of the distal lung. Our findings shed light on the factors influencing drug deposition, diffusion, and absorption in this critical area, offering insights into optimal delivery strategies. These findings underscore the pivotal roles of surfactant proteins, surface tension, and drug concentration in maintaining monolayer stability and facilitating drug adsorption, offering key insights to enhance pulmonary drug delivery systems.

 This study improves the development of more focused and efficient treatments for respiratory disorders by clarifying the drug-lung interaction at the molecular level. The results will contribute to a deeper understanding of the interaction mechanism between dexamethasone drugs and lung surfactants, particularly in elucidating how modifications to the spreading mechanism could potentially prevent monolayer collapse.