(380i) Modeling Passive and Active Transport of Antiretroviral Drugs across the Blood Brain Barrier for Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease that leads to dementia and is the 6^th leading cause of death in the United States. There is no known cure for AD and current treatments are aimed at relieving the symptoms of AD and slowing its progression. In drug development, one targeted mechanism of AD is neuroinflammation­­­­¹. Antiretroviral (ARV) drugs, initially developed for HIV, have recently been explored as a treatment option for AD due to their anti-inflammatory properties. However, a major challenge that remains is the ability to transport adequate amounts of ARVs across the blood-brain barrier (BBB). ARV transport across the BBB is made difficult by the presence of tight junctions in the endothelial cell membrane that comprises the BBB, as well as multi-drug resistant proteins imbedded in the membrane, such as P-glycoprotein (P-gp), that efflux ARVs and other drugs out of the brain and back into the blood².

Molecular dynamics (MD) simulations, coupled with enhanced sampling techniques, can provide unique insights into interfacial interactions between the BBB endothelial cell membrane and ARVs, and the underlying mechanisms of ARV transport across the BBB. This talk will describe MD simulations of ARVs interacting with and diffusing across a lipid membrane with a composition closely mimicking that of BBB endothelial cells. Steered molecular dynamics (SMD) have been employed to pull the ARVs across the BBB, leading to calculations of ARV transport properties that correlate with certain physicochemical properties of the ARVs. Molecular docking studies and MD simulations of ARVs interacting with P-gp will also be described, along with ARV/P-gp binding free energy calculations. Qualitative trends can again be drawn between the physicochemical properties of the ARVs and their binding affinity for P-gp. Overall, this research provides a comprehensive picture of passive and active transport of ARVs across the BBB, which may be used to guide the design of future AD therapeutics.

1. Zhu, C. cong et al. Advances in Drug Therapy for Alzheimer’s Disease. Med. Sci. 40, 999–1008 (2020).
2. Taylor, E. M. The impact of efflux transporters in the brain on the development of drugs for CNS disorders. Clinical Pharmacokinetics 41 81–92 (2002).