Using Autodock Tools for Automated Docking of Ligands to D2/D3 Receptors

Hayatshahi, Hamed
Kramer, Andrew
Liu, Jin
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Parkinson’s Disease (PD) is a neurodegenerative disorder of the substantia nigra, affecting roughly ten million individuals worldwide. Considering that the substantia nigra is the main player in dopamine production, progressive erosion of this structure has been shown to dramatically decrease the amount of dopamine in the brain. The direct pathway of movement responds to dopamine through the dopamine receptors, D2 and D3. Therefore, without dopamine, the brain struggles to produce movement, yielding many of the symptoms associated with PD: rigidity, tremors, shuffling gait. Current medications for PD increase dopamine concentrations or artificially activate the D2/D3 receptors; yet they are not without their side effects, most often causing loss of impulse control, confusion, and postural hypotension. Our goal is to better understand the selectivity mechanism of D2/D3 receptors in hopes of generating a more efficient medication in the future. By constructing a series of ligands with a similar molecular backbone but differing in various functional groups, we can utilize computer programming to find the activating energy of each ligand and compare the data in order to determine which functional group specifically activates either the D2 or D3 receptor. In this, roughly ninety distinctive ligands were drawn and converted to a three-dimensional product using Maestro. Utilizing Autodock Tools, these ligands were then computationally bound to both the D2 and D3 receptors, producing binding affinity for each ligand. In order to activate both the D2 and D3 receptors, a salt bridge must form between the protonated nitrogen of the nonaromatic ring of the ligand and aspartate residue 114 on the extracellular aspect of the receptor. Our findings revealed only thirty-six ligands successfully activating the D2 receptor in the correct orientation, and thirty-seven activating the D3 receptor. In total, the ligands drawn were more selective for the D3 receptor. From this data, we found a correlation between the presence of an ortho-methoxy group on the benzene ring of the ligand and its relationship to a serine residue on the receptor on D3R, producing a higher binding affinity. Therefore, by identifying the significance of this serine residue, we can better understand the selectivity of the D2/D3 receptors.