Design of Cannabinoid-Based Drugs for the Treatment of Parkinson's Disease

Parkinson’s disease (DP) is a neurodegenerative pathology that directly affects the dopaminergic neurons, decreasing the production of dopamine, resulting in motor and non-motor signs and symptoms. The treatments used have the function of reducing or alleviating the symptoms, but generate many adverse effects. In view of this, Pharmaceutical Chemistry conducts rational drug planning studies, and cannabinoids are being widely used to target neurological diseases. Therefore, the aim of this study is to plan a cannabinoid-derived drug for the treatment of DP. For this purpose, it was performed in the literature for cannabinoid molecules. Activity predictions were performed on the PASS and SEA servers. Their physicochemical properties were analyzed from the PubChem database. In the Qikprop software, the prediction of pharmacokinetic activities was performed and in DerekNexus, the toxicological properties of the molecules were observed. Molecular docking was done using the GOLD software. Prediction of synthetic accessibility was done by Sylvia software. In the results, 129 cannabinoid molecules were selected from the literature, of which 53 molecules showed antiparkinsonian action and 11 showed promise. On the SEA server only 6 molecules showed chemical similarity with targets of interest. Thus, 14 molecules were considered to have the best biological activities. The physicochemical properties of these 14 molecules were evaluated, in the results obtained, 3 cannabinoids presented 1 violation in Ro5. In the ADME/Tox prediction, only 11 molecules were selected, of which, 5 had ADME properties within the parameters and 9 do not show significant toxicity alerts. Four biological targets were used in the docking studies: the DDC enzyme, the MAO-B enzyme, the dopamine D3 receptor, and the COMT enzyme. Only 5 molecules were selected for this study, which were the ones that scored best in the virtual screening. After the validation of the targets used in the docking study, it was possible to analyze all the interactions between the molecules and the activity sites, which generated relevant information and complemented with the other biological activity studies. The evaluation of synthetic viability was performed, which generated average results. It then concluded that out of 129 initial cannabinoid molecules, only 6 of these were found to be the most promising, and the best drug candidates for the treatment of DP.