Pharmacophore modelling and molecular dynamics simulation to identify novel molecules targeting catechol-O-methyltransferase and dopamine D3 receptor to combat Parkinson’s disease

Parkinson’s disease is a neurological illness that slowly impairs a small number of neurons in the substantia nigra, a part of the brain. Dopamine, a substance (neurotransmitter) that disseminates signals to different regions of the brain and, when it functions correctly, coordinates smooth and balanced muscular activity, is typically produced by these cells. One-hand tremor is frequently the first sign of Parkinson’s disease. Loss of balance, stiffness, and delayed mobility are further symptoms. Proteins including catechol-O-methyltransferase and dopamine D3 receptors were taken into consideration as prospective therapeutic targets in this study. Two ligand-based pharmacophore models were generated with the help of compounds used for Parkinson’s disease which have structural similarity, screened from the first 16 compounds found in the drug bank. In the second case, 9 compounds that have similar structure to the compound istradefylline were selected. Based on docking score, intermolecular interactions, ADME (absorption, distribution, metabolism, and excretion) features, pharmacophore, and toxicity investigations, the inhibitors among the chosen compounds were found. Additionally, the chosen inhibitor underwent a 100 nanosecond molecular dynamics simulation with the two protein targets to determine its stability and binding affinity. The compound 3,4-Bis(1,3,5,6-heptatetraenyloxy) benzaldehyde was identified to be the most promising lead molecule in this analysis due to its better binding affinity, better pharmacophore properties, and greater stability. Hence, by targeting both specified proteins, the compound 3,4-Bis(1,3,5,6-heptatetraenyloxy) benzaldehyde should be beneficial against Parkinson’s disease.