## 4 Discussion
The results of the docking experiments are shown in Table 5. As can be seen, all the ligands present binding energies (\(\Delta\)Gbinding) between \(-\)5.278 and \(-\)7.303 kcal/mol, with the most negative energy corresponding to the complex formed between the ligand Ioflupane (009) and the dopamine transporter, with a binding free energy of \(-\)7.303 kcal/mol. The stability of this complex is based on the two H-bond interactions with Asp68 and Ser72, in addition to the \(\pi\)-\(\pi\) stacking interaction with Tyr355 (Sandwich Type) (Figure 9C). The second binding energy corresponded to the complex formed between Modafinil (001) and the dopamine receptor, with a binding free energy of \(-6.669\) kcal/mol. The stability of this complex is based on two \(\pi\)-\(\pi\) stacking interactions shared with Phe332 (T-Shaped and Sandwich Type) (Figure 9A). The third and fourth most negative binding free energies were found between the complexes formed between Procaine (003) (\(-6.452\) kcal/mol) and Armodafinil (010) (\(-6.436\) kcal/mol). The stability of the Procaine-dopamine transporter complex is based on one H-bond interaction with Asp79, and two \(\pi\)-\(\pi\) stacking interactions with Phe320 (Sandwich Type) and Phe326 (T-Shaped Type) (Figure 9B). The stability of the Armodafinil-dopamine transporter complex is based on two hydrogen bond (H-Bond) interactions shared with Leu459 (Figure 9D), in addition to the \(\pi\)-\(\pi\) stacking interaction with Phe462 (T-Shaped Type) (Figure 9D). The least stable complex of all those subjected to docking experiments was the one formed between the ligand Phenmetrazine (004) and the dopamine transporter, as well as the least stable complex, corresponding to Phentermine (002) and the dopamine transporter. These two ligands were oriented away from the active center of the protein with loss of non-covalent interactions (Figure 10). Figure 9: Representation of the interactions of the ligands in the active center of the dopamine transporter: (**A**) Modafinil (001), (**B**) Procaine (003), (**C**) Ioflupane (009), and (**D**) Armodafinil (010). Below, we present a detailed comparison of the results of our docking experiments (\(\Delta\)Gbinding and RMSD) with recently published data from computational and experimental studies. This comparison serves to validate the consistency and reliability of our findings. For example, a recent study developed robust QSAR models on approximately 61 DAT inhibitors, including drugs similar to ours, and obtained \(\Delta\)Gbinding values very similar to ours. Phenmetrazine (L-004) in this study behaved very similarly to ours, with \(\Delta\)Gbinding \(\approx-6.8\) kJ/mol [78]. To support the validity of our data, we compared the docking results with recent experimental affinities in the scientific literature. Modafinil has been estimated to have a Ki \(\approx 2600\) nM (\(\approx\)2.6 \(\upmu\)M) per human DAT, which is in agreement with our finding of \(\Delta\)Gbinding \(\approx-5.99\) kJ/mol, reflecting a low affinity for the dopamine receptor, a result that is in agreement with our study. Furthermore, an analogous relationship between experimental affinity in this study and the binding energies observed in our set of molecules (with several ligands in the range \(-7.0\) to \(-7.5\) kJ/mol with RMSD < 2 A) has been found, corroborating the predictive power of our docking experiments [79]. Molecular dynamics simulations provide us with information about the behavior of ligand-protein complexes over time at the atomic level [70; 80; 81; 82]. In our case, they also allow us to determine the stability of the systems and whether the interactions found in the docking experiments are maintained over time. To this end, we analyzed several parameters obtained from the trajectory, which will be discussed below. One of the important parameters when analyzing the stability of ligand-protein complexes over time is the RMSD [47; 83; 84].