(360az) The Role of Antiretroviral Therapeutics As Both Inhibitors and Substrates of P-Glycoprotein

Transporting drugs across the blood-brain barrier (BBB) is a major crux in developing pharmaceuticals for treating neurological disorders and infections in the brain. Due to the difficulty of reaching effective therapeutic levels of antiretroviral (ARV) drugs in the brain, HIV is able to quickly establish an infection in the brain, leading to neurological dysfunction over time and a viral population that is difficult to ever fully eradicate. The presence of efflux proteins embedded in the endothelial cells of the BBB is one reason that crossing the BBB is such a hindrance to small molecule drug transport. The most prevalent efflux protein in the BBB is the ATPase protein, P-glycoprotein (P-gp). Protease inhibitors (PIs) that are commonly used to treat HIV are all known substrates of P-gp. However, some PIs, such as ritonavir, also behave as inhibitors of P-gp. A better understanding of the interactions between P-gp and PIs, both as substrates and inhibitors, is necessary to design ARVs that can more readily pass through the BBB and penetrate the brain microenvironment.

Molecular docking and molecular dynamics (MD) simulations are powerful and crucial computational tools for understanding how small molecule drugs, such as PIs, interact with proteins, such as P-gp. Our molecular docking results show that inhibitory PIs, such as ritonavir, bind in the ATP active site of P-gp, as well as in the substrate binding domain. The former binding location indicates that competitive inhibition is a possible mechanism of PI-based inhibition of P-gp. Comparatively, our results show that PIs that are not known to inhibit P-gp, such as saquinavir, only bind in the substrate binding domain of P-gp. MD simulations provide further insight into the free energy of binding of each PI to P-gp, and how binding of the PIs at different sites on P-gp differentially impacts the structure and dynamics of P-gp in solution. In this work, we also describe computational results can be fully understood in the context of experimental inhibition data and the bioavailability of different PIs. Overall, our molecular level insights on PI/P-gp binding may serve as a guide for designing new therapeutics that can inhibit or avoid binding to P-gp altogether, improving our ability to deliver ARVs to the brain for treating the neurological complications of HIV infection.