High Throughput in Silico Identification of α-Syn Aggregation Inhibitors for Parkinson's Disease
DOI:
https://doi.org/10.47611/jsrhs.v10i4.2096Keywords:
Alpha Synuclein, Parkinson's Disease, Molecular Docking, Treatment Identification, High Throughput ScreeningAbstract
Parkinson’s Disease (PD) is caused by the depletion of dopamine as a result of aggregates formed by a protein called alpha-synuclein (a-syn), which are toxic and kill dopamine neurons in the substantia nigra pars compacta brain region. PD currently only has some symptomatic treatments that lose effectiveness over time. The purpose of this study was to identify drugs that bind to the fibril forming segment of the non-amyloid beta component (NAC) domain of neuronal membrane bound a-syn. These drugs will inhibit other a-syn monomers from binding and prevent further a-syn aggregation, slowing the progression of PD.
Molecular docking was used to run a high throughput screening of 646 FDA approved drugs. The interactions between each drug and a-syn were analyzed and compared to those of Baicalein and SynuClean-D, two drugs that can inhibit a-syn aggregation by binding with the NAC domain but are not FDA approved.
13 drugs were identified that can potentially be used to inhibit membrane bound a-syn aggregation and were almost 6 times more potent than Baicalein and 10 times more potent than SynuClean-D at binding with a-syn’s NAC domain. The Blood Brain Barrier (BBB) penetrability of these top 13 drugs was assessed, indicating the drugs with a higher likelihood of penetrating the BBB. The results of this study appoint Telmisartan and Ibrutinib as FDA approved, BBB penetrable drugs that could inhibit membrane bound a-syn aggregation, slowing the progression of PD. Verifying these results through in vitro experiments can result in identifying a promising treatment for PD.
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