The evaluation of novel metal -based compounds as potential BACE1 ligands.
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The proposed primary cause of Alzheimer’s disease (AD) is the cleavage of the Amyloid-β precursor protein by the β- Amyloid cleavage enzyme 1 (BACE1). As such it has been proposed that inhibiting this enzyme would help reduce the formation of Aβ plaques and slow down the progression of the disease. However, there is currently no treatment available that slows down the progression of AD and current drugs on the market only treat the symptoms of the disease. Metal-based compounds have been studied extensively for use as anticancer treatments. Success in the of these metal-based compounds have introduced new avenues in drug development and as such, there have been studies conducted on the introduction into metal-based compounds as potential AD drug candidates. In this study, 13 novel metal-based compounds were evaluated using five simple assessment techniques to determine potential BACE1 ligands. Molecular docking studies were able to predict that compound 12 was able to bind readily with BACE1 as it had a greater docking score (-4.630) which correlated with the thermal shift assay as the ΔTm of 9.1 ⁰C was compared to the other compounds. Compounds 7 and 13 were found to be aggregating compounds when results of the chymotrypsin assay were assessed. In addition, the lack of inhibition in the presence and absence of detergent in the chymotrypsin assay was able to determine specificity of these metal-based compounds to the BACE1 protein. Furthermore, the DNA cleavage assay determined that copper-containing compounds 9, 10 and 11 were able to cause scissions in supercoiled plasmid DNA. Theoretical predictions of the physiochemical properties were evaluated to determine probable CNS/oral drug candidates according to Lipinski’s rule of 5 and Veber’s rules. All results obtained in this study predicted most favourable results with seven compounds producing an RO5 score of 4 thus making them potential BACE1 ligands with probable CNS/oral drug candidate properties and with fewer toxic effects. Furthermore, the chymotrypsin assay revealed that compound 13 was an aggregator and that compound 7 had binding affinities to both BACE1 and chymotrypsin. Overall assessment of these compounds has revealed that the compounds with the most favourable properties and an oral and CNS drug candidate as well as a good BACE1 ligand was compound 6. In addition, the overall positive outcomes of the molecular docking and TSA indicate that metal-based compounds have great potential in the drug design and discovery of new drug candidates for the treatment of AD.