Interaction of Glucocorticoid Drug with Model Lung Surfactant Monolayers: Molecular Dynamics Simulation Approach

Islam, Mohammad Zohurul

Interaction of Glucocorticoid Drug with Model Lung Surfactant Monolayers: Molecular Dynamics Simulation Approach

Islam, Mohammad Zohurul

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Publication Type:: Thesis
Issue Date:: 2022

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Field	Value	Language
dc.contributor.author	Islam, Mohammad Zohurul
dc.date.accessioned	2023-01-13T01:20:17Z
dc.date.available	2023-01-13T01:20:17Z
dc.date.issued	2022
dc.identifier.uri	http://hdl.handle.net/10453/164944
dc.description	University of Technology Sydney. Faculty of Engineering and Information Technology.	en_US.UTF-8
dc.description.abstract	Glucocorticoids are used to treat a wide range of inflammatory conditions, including lung diseases such as asthma, respiratory allergies, and chronic obstructive pulmonary disease. The use of glucocorticoids via oral, intravenous, or topical administration causes side effects by systemic pathway. The lung airways are the most effective routes for corticosteroid drug administration by inhalation or nebulisation into upper and the peripheral airways at alveoli, especially for drugs with low solubility and poor bioavailability by avoiding systemic side effects. The benefits of corticosteroid administration by inhalation over other modes of drug administration are corticosteroid delivery to the target area with relatively low systemic adsorption, avoiding side effects of the drug, and reducing drug wastage. Understanding the molecular interaction of corticosteroid drugs with the lung surfactant monolayer is critical for the effective dosing and delivery of existing drugs. However, the molecular-level mechanism of how drugs interact with the monolayer is poorly understood. Part of that is a lack of a molecular-level model that mimics the physicochemical properties of the monolayer. This study carried out coarse-grained biomolecular simulations to investigate the molecular interactions between lung surfactant and several clinically relevant glucocorticoid drugs (prednisolone, mometasone, cortisone and hydrocortisone). The major components of the lung surfactant, namely phospholipids, cholesterol, and the surfactant proteins B and C (SP-B and SP-C), were used to mimic the structural and dynamical properties of the monolayer at the air/water interface. The effect of drug concentrations on the structural and dynamical properties and phase behaviour of the monolayer were characterised. In addition to these, the role of individual components of lung surfactants on the diffusion of corticosteroid drugs was studied. The outcomes from this study demonstrate that corticosteroid drug has a concentration-dependent effect on the structural and dynamical properties of monolayer for a critical drug concentration (~5-6% w/w), and structural damage of the monolayer has been seen once the drug exceeds the critical concentration. Surfactant protein and drug concentration both contribute to influence the monolayer instability. Cholesterol has a major impact on controlling lung surfactant fluidity. Precise spreading of the drug over the monolayer is found at higher surface tension. The findings will provide a better understanding of the interaction mechanism between corticosteroid drugs and lung surfactants, particularly how altering the spreading mechanism might be used to prevent monolayer collapse. The current Ph.D. project will also provide guidelines for the future design of effective corticosteroid dosing to treat various lung diseases.	en_US.UTF-8
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US.UTF-8
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/164944/2/02whole.pdf
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	au.edu.uts.lib/ppc
dc.title	Interaction of Glucocorticoid Drug with Model Lung Surfactant Monolayers: Molecular Dynamics Simulation Approach	en_US.UTF-8
dc.type	Thesis
utslib.copyright.status	open_access	*

Abstract:

Glucocorticoids are used to treat a wide range of inflammatory conditions, including lung diseases such as asthma, respiratory allergies, and chronic obstructive pulmonary disease. The use of glucocorticoids via oral, intravenous, or topical administration causes side effects by systemic pathway. The lung airways are the most effective routes for corticosteroid drug administration by inhalation or nebulisation into upper and the peripheral airways at alveoli, especially for drugs with low solubility and poor bioavailability by avoiding systemic side effects. The benefits of corticosteroid administration by inhalation over other modes of drug administration are corticosteroid delivery to the target area with relatively low systemic adsorption, avoiding side effects of the drug, and reducing drug wastage. Understanding the molecular interaction of corticosteroid drugs with the lung surfactant monolayer is critical for the effective dosing and delivery of existing drugs. However, the molecular-level mechanism of how drugs interact with the monolayer is poorly understood. Part of that is a lack of a molecular-level model that mimics the physicochemical properties of the monolayer. This study carried out coarse-grained biomolecular simulations to investigate the molecular interactions between lung surfactant and several clinically relevant glucocorticoid drugs (prednisolone, mometasone, cortisone and hydrocortisone). The major components of the lung surfactant, namely phospholipids, cholesterol, and the surfactant proteins B and C (SP-B and SP-C), were used to mimic the structural and dynamical properties of the monolayer at the air/water interface. The effect of drug concentrations on the structural and dynamical properties and phase behaviour of the monolayer were characterised. In addition to these, the role of individual components of lung surfactants on the diffusion of corticosteroid drugs was studied. The outcomes from this study demonstrate that corticosteroid drug has a concentration-dependent effect on the structural and dynamical properties of monolayer for a critical drug concentration (~5-6% w/w), and structural damage of the monolayer has been seen once the drug exceeds the critical concentration. Surfactant protein and drug concentration both contribute to influence the monolayer instability. Cholesterol has a major impact on controlling lung surfactant fluidity. Precise spreading of the drug over the monolayer is found at higher surface tension. The findings will provide a better understanding of the interaction mechanism between corticosteroid drugs and lung surfactants, particularly how altering the spreading mechanism might be used to prevent monolayer collapse. The current Ph.D. project will also provide guidelines for the future design of effective corticosteroid dosing to treat various lung diseases.

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