School of Mechanical and Mechatronic Engineering, University of Technology Sydney, 15 Broadway, Ultimo, NSW, 2007, Australia.
School of Life Sciences, University of Technology Sydney, 15 Broadway, Ultimo, NSW, 2007, Australia.
J Mol Graph Model. 2022 Mar;111:108084. doi: 10.1016/j.jmgm.2021.108084. Epub 2021 Nov 20.
Mometasone is an investigational anti-inflammatory steroidal drug to treat inflammation via pulmonary administration. For steroid drugs to be effective they need to be adsorbed by lung surfactants, a thin monolayer at the air-water interface in alveoli that reduces surface tension. Information on the molecular-level interactions of the drug with lung surfactants is useful to understand the mechanism of adsorption. In this study, we use coarse-grained molecular dynamics simulation to understand the concentration-dependent effect of mometasone on a lung surfactant monolayer (LSM) composed of lipids and surfactant proteins, under two different breathing conditions (exhalation, at surface tension 0 mNm and inhalation, surface tension 20-25 mNm). A series of fixed-APL and fixed-surface tension simulations were used to demonstrate that in the absence of drugs, the model LSM reproduces the surface tensions for the compressed and expanded states, as well as compressibility at different surface tensions. In-depth analysis of simulations of a LSM in the presence of five different drug concentrations shows that mometasone alters the structure and dynamics of the LSM in a concentration-dependent manner. Mometasone induces a collapse in the monolayer that is affected by the surfactant protein and surface tension. Overall, these findings suggest that the surfactant proteins, surface tension and drug concentration are all critical components affecting monolayer stability and drug adsorption. The outcomes of this study may be beneficial for a more in-depth understanding of how mometasone is adsorbed by lung surfactants.
莫米松是一种研究中的抗炎类固醇药物，通过肺部给药来治疗炎症。为了使类固醇药物有效，它们需要被肺表面活性剂吸附，肺表面活性剂是肺泡中空气-水界面的一层薄的单层，可降低表面张力。关于药物与肺表面活性剂之间分子水平相互作用的信息有助于理解吸附机制。在这项研究中，我们使用粗粒化分子动力学模拟来了解莫米松在两种不同呼吸条件（呼气，表面张力为 0 mNm 和吸气，表面张力为 20-25 mNm）下对由脂质和表面活性剂蛋白组成的肺表面活性剂单层（LSM）的浓度依赖性影响。一系列固定 APL 和固定表面张力模拟用于证明在没有药物的情况下，模型 LSM 再现了压缩和扩展状态的表面张力以及不同表面张力下的可压缩性。在存在五种不同药物浓度的 LSM 的模拟的深入分析表明，莫米松以浓度依赖的方式改变 LSM 的结构和动力学。莫米松诱导单层坍塌，这受表面活性剂蛋白和表面张力的影响。总体而言，这些发现表明表面活性剂蛋白、表面张力和药物浓度都是影响单层稳定性和药物吸附的关键因素。这项研究的结果可能有助于更深入地了解莫米松如何被肺表面活性剂吸附。
