(691d) Modeling Complex Lipid Bilayers to Investigate the Diffusion of Antiretroviral Drugs across the Blood-Brain Barrier

Transporting drugs across the blood-brain barrier (BBB) is a major hurdle in developing pharmaceuticals for the treatment of neurological diseases. Consequently, HIV infection in the brain, which leads to neurocognitive dysfunction, is difficult to effectively treat because antiretroviral (ARV) drugs are unable to reach therapeutic levels in the brain. One reason that the diffusion of small molecule drugs, such as ARVs, into the brain is hindered is due to the unique membrane lipid composition of the endothelial cells that make up the BBB. Drugs specifically engineered to have increased permeability across the BBB hold significant promise for treating HIV infection in the brain and preventing progression of neurocognitive disorders due to HIV. While the permeability of the BBB has been studied both in vivo and in vitro, in silico analysis is necessary for targeted drug design. Molecular dynamics (MD) simulations, coupled with enhanced sampling techniques such as steered molecular dynamics (SMD), can provide unique insights into key interfacial interactions between the BBB endothelial cell membrane and ARVs.

Herein, we describe the use of MD simulations to model passive diffusion through a complex lipid bilayer composed of 13 unique species of phospholipids and cholesterol, providing an accurate representation of the human BBB endothelial cell membrane. Previous studies using MD to model the BBB have generally only considered a few phospholipid types, preventing a detailed investigation into the interactions between different lipid head groups and hydrophilic chains and ARVs. Results from our simulations show that different ARVs have preferred interactions with different types of lipids in the membrane, implying that simulating the full compositional complexity of the BBB is crucial to fully characterizing the barriers to ARV transport into the brain. We describe the use of SMD to calculate the work needed to pull each ARV through the bilayer, serving as a proxy for membrane permeability that is used to rank the brain-penetrating capabilities of the different ARVs studied. Overall, our results provide a deeper understanding of how different chemical groups and physicochemical properties impact the diffusion of ARVs across the BBB, leading to new insights into how to rationally design therapeutics that can more readily penetrate and treat HIV infection in the brain.