The effect of phenylthiophene as an allosteric pharmacophore on the affinity of phenylpiperazine derivatives for dopamine receptors

Purpose: Dopamine receptors are important therapeutic targets in treatment of many neurological diseases such as schizophrenia and Parkinson's disease. Compounds like phenylpiperazine derivatives that selectively target D3R subtype have shown significant clinical benefits. The selectivity of these compounds for D3R over D2R is shown to increase when a phenylthiophene is added as a second pharmacophores. Here, we used a computational approach to see how the second pharmacophore affects the affinity of these ligands. Method: In an effort to evaluate the difference of these compounds, docking on the crystal structure of D2R and D3R was completed using AutoDock vina after the ligands were prepared for docking with Autodock tools. Results: The binding energies from the docking poses followed expected trend that the addition of phenylthiophene compounds would increase the affinity for D3R. We further studied the binding of the more selective ligands that have 3,5-dicholoro and 3CN substitution on the phenylpiperazine to analyze the important interactions that stabilize the D3R binding. Conclusion: Studying compounds that have higher selectivity towards D3R shed light on important interactions that the phenylthiophene can have with D3R. The added phenylthiophene seems to potentially interact with Tyr7.35 and the ECL2 region in D3R. Additional investigation is needed to determine the neurological applicability of these compounds.