Identifying neprilysin-inhibiting FDA approved drugs as possible risk factors for Alzheimer's disease

Although Alzheimer’s disease is the most common type of dementia, unfortunately, safe and effective treatments that could slow the progress of this progressive neurodegenerative disease are still lacking. This amplifies the importance of preventing this disease and, thus, identifying its risk factors. It has already been known that various drugs may increase the risk for Alzheimer’s disease. Here, we searched for approved drugs that may increase this risk through inhibiting neprilysin. Neprilysin is the rate-limiting enzyme in the amyloid beta clearance pathway and is even able to catalyze unphysiologically large amount of amyloid beta. Inhibitors of neprilysin may increase the risk of Alzheimer’s disease and exacerbate its progress via increasing the amounts of the accumulated amyloid beta and its secondary products.

In this study, after predicting the blood-brain barrier (BBB) penetration of approved drugs and their metabolites, we used various computational tools to identify potential inhibitors of neprilysin among them. These tools included various structure-based approaches like docking with AutoDockZn, PLANTS, FlexX, Fitted, Molegro, and Flare and rescoring with these scoring functions: Convex-PL, GNINA, JamdaScorer, KORP-PL, RF-Score-VS, Rank Score, dG, VScore. The reliability of these methods was assessed by investigating the correlations of their predictions with experimental measurements. We also used these ligand-based approaches: 2D-QSAR modelling and similarity comparison based on feature trees.

These in silico tools suggested that several drugs deserve to be further investigated beacuase of their considerable binding affinity to neprilysin and BBB penetration: aripiprazole, etoricoxib, nabumetone, fentiazac, clorotepine, pitolisant, and chloroquine. Other drugs whose BBB penetration were not predicted to be much high yet their chronic or common use may lead to consequential inhibition of neprilysin can be added to this list, like glyburide, lisinopril, cilazapril, fosinopril, prucalopride, ibersartan, valsartan, and montelukast. Further investigations, including in vitro, animal, and human investigations, can help mitigate the huge and rising societal and economic burden of Alzheimer’s disease globally.