Virtual screening for MAO-B inhibitors, a molecular target in Parkinson's disease

Abstract

Introduction. Parkinson's disease (PD) is a neurological pathology characterized by chronic and progressive degeneration of dopaminergic neurons in the substantia nigra pars compact (SNpc) and is the second most common neurodegenerative disorder, with age being the main risk factor. L-3,4-dihydroxyphenylanine (L-DOPA) has been widely used as the main treatment for PD. However, the majority of patients chronically treated with L-DOPA have adverse motor and psychiatric effects. Thus, several therapeutic strategies have been tested in order to replace striatal dopamine in a more physiological way, among them the use of Monoamine Oxidase B (MAO-B) inhibitors. Objective. To obtain theoretical models of new MAO-B inhibitors, with physico-chemical characteristics for the development of drugs for the treatment of PD. Method. A virtual screening was performed based on the structure of the crystallographic inhibitor Safinamide, with filter application to evaluate the passage through the blood-brain barrier, as well as docking simulations and re-docking validation. Results. The theoretical inhibitors were: (7R,8S,8'R)-7-Hydroxy-3,4,3',4'-tetramethoxy-8,8'-neolignan, Oxovirolin and 3-oxo-skimmiarepin, which exhibited affinity to the MAO-B binding site better or similar to that of the reference inhibitor. All compounds exhibited physicochemical properties favorable for oral bioavailability, according to the descriptors of Lipinski and Veber. Conclusion. The theoretical inhibitors found are potential targets for planning and designing drugs for Parkinson's Disease. However, because it is an in silico study, it is necessary that more research and tests are done to evaluate in vitro and, later, in vivo the behavior of these molecules.