*3.4. Molecular Docking Studies*

To find the optimal docking pose, the six CT complexes were docked against three protein receptors: serotonin, dopamine, and TrkB kinase. For comparison, the SRX drug (donor moiety) was employed as a control. The potential binding energy of CT complexes was higher than that of SRX in all receptors, according to the molecular docking of these six complexes (Table 2).


**Table 2.** The docking score of six synthesized CT complexes docked with three receptors [serotonin (PDB ID: 6BQH), dopamine (PDB ID: 6CM4), and TrkB kinase (PDB ID: 4ASZ)].

Of the six CT complexes studied, [(SRX)(TCNQ)] exhibited the highest docking energy values. [(SRX)(TCNQ)] had predicted binding energies of −9.3, −9.9, and −8.2 kcal/mol with serotonin, dopamine, and TrkB kinase receptors, respectively. The binding energy of [(SRX)(TCNQ)]-dopamine (CTcD) is higher than that of serotonin and the TrkB kinase receptors, indicating a stronger link. The optimal docking pose of (CTcD) is shown in Figure 5, and the docking data are listed in Table 3.

**Table 3.** The interactions of SRX-TCNQ and SRX with dopamine (6CM4).


The [(SRX)(TCNQ)]-dopamine (CTcD) shows that the amino acid residues, including Tyr416 and Trp413, formed hydrogen bond interactions (Figure 8a). There are other interactions between Leu94, Trp100 (π-Alkyl), Phe189 (π-Sigma), Asp114 (π-Anion), and Ile184 (halogen-fluorine) [59]. The theoretical binding energies of SRX with the serotonin, dopamine and TrkB kinase receptors were −7.3, −7.4, and −6.0 kcal/mol, respectively, after molecular docking. The [SRX]-dopamine (SRXD) receptor had a stronger connection than the serotonin and TrkB kinase receptors due to its greater binding energy value. *Molecules* **2022**, *27*, x 11 of 21

**Figure 8.** Three-dimesnional representation of interactions for dopamine docked with (**a**) [(SRX)(TCNQ)] and (**b**) [SRX]. **Figure 8.** Three-dimesnional representation of interactions for dopamine docked with (**a**) [(SRX)(TCNQ)] and (**b**) [SRX].

pleasure [60]. Figure 9 shows two-dimensional depictions of ligand–receptor interactions. Figures 10 and S2 show the hydrophobic, ionizability, aromatic, and hydrogen bond sur-

faces at the interaction location of [(SRX)(TCNQ)] and dopamine, respectively.

Given the growing evidence that DA transmission assists antidepressant therapeutic goals [60], this augmentation of transmission could have clinical implications. This is be-

The interaction between SRX and dopamine is illustrated in Figure 8b. The amino acid residues, including Ser409 and Thr412, formed hydrogen bond connections between SRX and dopamine. There were also interactions between Tpr100, Val91 (π-alkyl), and Tyr416 (π-sigma). These data indicate that the [(SRX)(TCNQ)] complex binds to the three protein receptors more efficiently than the reactant donor (SRX) alone and that the CTcD has the highest binding energy value. TNCQ is a powerful electron acceptor that forms charge transferring chains due to the existence of its four cyano groups and π-conjugation bonds. This facilities the increase in interactions (such as H-bond, π-Alkyl, π-Sigma, π-Anion, along with SRX) with receptors. **Figure 8.** Three-dimesnional representation of interactions for dopamine docked with (**a**) [(SRX)(TCNQ)] and (**b**) [SRX]. Given the growing evidence that DA transmission assists antidepressant therapeutic

*Molecules* **2022**, *27*, x 11 of 21

Given the growing evidence that DA transmission assists antidepressant therapeutic goals [60], this augmentation of transmission could have clinical implications. This is because the majority of modern antidepressants do not boost dopamine neurotransmission [60]. One reason for DA's significance is that it regulates motivation, concentration, and pleasure [60]. Figure 9 shows two-dimensional depictions of ligand–receptor interactions. Figure 10 and Figure S2 show the hydrophobic, ionizability, aromatic, and hydrogen bond surfaces at the interaction location of [(SRX)(TCNQ)] and dopamine, respectively. goals [60], this augmentation of transmission could have clinical implications. This is because the majority of modern antidepressants do not boost dopamine neurotransmission [60]. One reason for DA's significance is that it regulates motivation, concentration, and pleasure [60]. Figure 9 shows two-dimensional depictions of ligand–receptor interactions. Figures 10 and S2 show the hydrophobic, ionizability, aromatic, and hydrogen bond surfaces at the interaction location of [(SRX)(TCNQ)] and dopamine, respectively.

**Figure 9.** Two-dimensional representation of interactions of dopamine docked with (**a**) CT complex and (**b**) SRX.
