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

## TL;DR

This study explores PCPMA derivatives as selective ligands for the dopamine D3 receptor using computational methods to guide future drug development.

## Contribution

The study introduces a novel theoretical framework combining 3D-QSAR, docking, and molecular dynamics to design D3R-selective ligands.

## Key findings

- 3D-QSAR models showed steric, electrostatic, and hydrophobic fields are crucial for PCPMA-D3R binding.
- Four novel PCPMAs were predicted to have stronger D3R affinity based on computational analysis.
- Molecular dynamics and free energy calculations confirmed strong ligand-receptor interactions in the binding pocket.

## Abstract

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.