Dopamine D
3 receptor (D
3R) is a key receptor for regulating motor, cognitive, and other functions. In this study, 50 2-phenylcyclopropylmethylamine (PCPMA) derivatives with good selectivity for D
3R were investigated using a three-dimensional quantitative structure–activity relationship (3D-QSAR) method. The
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Dopamine D
3 receptor (D
3R) is a key receptor for regulating motor, cognitive, and other functions. In this study, 50 2-phenylcyclopropylmethylamine (PCPMA) derivatives with good selectivity for D
3R were investigated using a three-dimensional quantitative structure–activity relationship (3D-QSAR) method. The CoMFA and CoMSIA model results showed good predictive ability, as evidenced by high r
2 and q
2 values. 3D-QSAR results showed that steric, electrostatic, and hydrophobic fields played important roles in the binding of PCPMAs to D
3R. Based on above results, four novel PCPMAs were designed, which were predicted to have a stronger affinity with D
3R. Molecular docking combined with 300 ns molecular dynamics simulations were performed to reveal the mode of interaction between D
3R and PCPMAs. Additionally, a combination of free energy calculations and energy decomposition results indicated strong interaction between the ligands and residues in the binding pocket of the D
3 receptor. This work provides suggestions for exploring more selective D
3R ligands, and this theoretical framework also lays the foundation for future experimental investigations to evaluate the pharmacological characteristics and binding affinities of novel derivatives.
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