In the Master's thesis, we computationally designed dual inhibitors of butyrylcholinesterase and mitogen-activated protein kinase p38α for the treatment of Alzheimer's disease. This disease is a pressing problem in developed countries where life expectancy is increasing. Current treatment is with acetylcholinesterase inhibitors, which can have undesirable side effects. Research has shown that selective butyrylcholinesterase inhibitors would be more effective in the treatment of Alzheimer's disease, because given its physiological role, they predict that such inhibitors would have fewer unwanted side effects. Part of the pathogenesis of Alzheimer's disease is neuroinflammation, which could be prevented by inhibitors of mitogen-activated protein kinase p38α.
With molecular docking of commercially available known inhibitors of mitogen-activated protein kinase p38α into the active site of butyrylcholinesterase, we selected eleven compounds for ordering according to our criteria. Biochemical assay confirmed the activity of one compound, MPB01, on both targets. MPB01 inhibited butyrylcholinesterase in the low micromolar range and mitogen-activated protein kinase p38α in the nanomolar range. In addition, it selectively inhibited butyrylcholinesterase compared to acetylcholinesterase. We docked the compound in the active site of both targets and prepared several pharmacological models for the next stage of virtual screening. Validation of the models was carried out with a library of biochemically evaluated compounds on both targets, which were appropriately divided into a set of active and a set of inactive compounds. We also added computationally generated decoys to the library of inactive compounds. Based on the validation results, we selected one pharmacophore model for filtering of the library of all stock compounds. We docked the hits to the active site of both targets, narrowed the selection of compounds based on scoring function and diversity, and selected twenty-one compounds for ordering. Among the selected compounds, no compound showed improved activity compared to the original hit, which represents a good starting point for the further development of dual inhibitors for the treatment of Alzheimer’s disease.
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