2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as D3R-Selective Ligands for 3D-QSAR, Docking and Molecular Dynamics Simulation Studies

Dopamine D3 receptor (D3R) is a key receptor for regulating motor, cognitive, and other functions. In this study, 50 2-phenylcyclopropylmethylamine (PCPMA) derivatives with good selectivity for D3R 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 r2 and q2 values. 3D-QSAR results showed that steric, electrostatic, and hydrophobic fields played important roles in the binding of PCPMAs to D3R. Based on above results, four novel PCPMAs were designed, which were predicted to have a stronger affinity with D3R. Molecular docking combined with 300 ns molecular dynamics simulations were performed to reveal the mode of interaction between D3R 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 D3 receptor. This work provides suggestions for exploring more selective D3R ligands, and this theoretical framework also lays the foundation for future experimental investigations to evaluate the pharmacological characteristics and binding affinities of novel derivatives.