Discovery of potential neurodegenerative inhibitors in Alzheimer’s disease by casein kinase 1 structure-based virtual screening

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by loss of neurons. Pathological patterns include the presence of amyloid plaques (accumulation of amyloid-β protein fragments) and neurofibrillary tangles. Only two major groups of drugs are used in Alzheimer’s disease’s treatment: cholinesterase inhibitors and antagonists of N-methyl-D-aspartate receptor. The phosphorylation of proteins by protein kinases constitutes one of the major mechanism by which cells use to regulate their metabolism. Imbalance in these activities is related to a series of diseases. The high number of casein kinase 1 isoforms found in Alzheimer’s disease brains and its association with neurodegenerative markers indicates their participation in the final stages of Alzheimer’s disease degeneration. In this study, it was employed structure-based virtual screening techniques in a chemical space of 500 thousand chemical structures. The ten chemical structures with the best inhibitory profile for casein kinase 1 were then selected for activity and toxicity predictions. The compounds 11 (ZINC48488295), 14 (ZINC04869366) and 17 (ZINC4412706) presented significant potential for CK1δ enzyme inhibition.