*3.5. Molecular Dynamics Simulation*

For the 100 ns simulation run, the best-docking position for SRXD and CTcD with the highest docking score was used. The RMSD of molecular dynamics data was calculated to investigate structural stability. After 45 ns and 60 ns, respectively, SRXD and CTcD established constant conformation with an appropriate RMSD value of 2.85 and 3.56, respectively (Figure 11).

**Figure 9.** Two-dimensional representation of interactions of dopamine docked with (**a**) CT com-

*Molecules* **2022**, *27*, x 12 of 21

plex and (**b**) SRX.

**Figure 10.** Representation of (**a**) hydrogen binding surface, (**b**) hydrophobic surface, (**c**) aromatic surface, and (**d**) ionizability surface; between dopamine and CT complex. **Figure 10.** Representation of (**a**) hydrogen binding surface, (**b**) hydrophobic surface, (**c**) aromatic surface, and (**d**) ionizability surface; between dopamine and CT complex. *Molecules* **2022**, *27*, x 13 of 21

**Figure 11.** The root mean square deviation (RMSD) of solvated receptor backbone and ligand complex during 100 ns MD simulation [SRXD complex (black) and CTcD complex (green)]. CTcD (green), and (**b**) SRXD (blue). **Figure 11.** The root mean square deviation (RMSD) of solvated receptor backbone and ligand complex during 100 ns MD simulation [SRXD complex (black) and CTcD complex (green)].

As indicated previously, <3.0 Å is the most acceptable RMSD value range, which indicates better system stability [61]. This finding shows that the CTcD develops a more

**Figure 12.** Superimposed structure after simulation of unbound dopamine receptor (red) and (**a**)

chains closer and reduce the gap between them, as shown in Figure 12 [62].

As indicated previously, <3.0 Å is the most acceptable RMSD value range, which indicates better system stability [61]. This finding shows that the CTcD develops a more stable combination. The findings revealed that ligand-receptor interactions bring protein chains closer and reduce the gap between them, as shown in Figure 12 [62]. As indicated previously, <3.0 Å is the most acceptable RMSD value range, which indicates better system stability [61]. This finding shows that the CTcD develops a more stable combination. The findings revealed that ligand-receptor interactions bring protein chains closer and reduce the gap between them, as shown in Figure 12 [62].

plex during 100 ns MD simulation [SRXD complex (black) and CTcD complex (green)].

**Figure 11.** The root mean square deviation (RMSD) of solvated receptor backbone and ligand com-

*Molecules* **2022**, *27*, x 13 of 21

**Figure 12.** Superimposed structure after simulation of unbound dopamine receptor (red) and (**a**) CTcD (green), and (**b**) SRXD (blue). **Figure 12.** Superimposed structure after simulation of unbound dopamine receptor (red) and (**a**) CTcD (green), and (**b**) SRXD (blue). *Molecules* **2022**, *27*, x 14 of 21

The average distance and standard deviation for all amino acid pairs between two conformations were calculated using RR distance maps [63]. In Figure 13, the patterns of spatial interactions are depicted using the RR distance maps [64]. The average distance and standard deviation for all amino acid pairs between two conformations were calculated using RR distance maps [63]. In Figure 13, the patterns of spatial interactions are depicted using the RR distance maps [64].

**Figure 13.** RR distance map between unbound dopamine receptor and after simulation for SRXD (**a**), and CtcD (**b**). **Figure 13.** RR distance map between unbound dopamine receptor and after simulation for SRXD (**a**), and CtcD (**b**).

On the map, the white oblique represents the zero distance between two amino acid residues, whereas the red and blue elements depict residue pairs with the biggest distance deviations between the two forms. The average radius of gyration (Rg) value of 28.75 and

decreased, indicating that the structures became more compact (Figure 14).

On the map, the white oblique represents the zero distance between two amino acid residues, whereas the red and blue elements depict residue pairs with the biggest distance deviations between the two forms. The average radius of gyration (Rg) value of 28.75 and 28.52 Å was observed for SRXD and CTcD, respectively. Along the simulation time, Rg decreased, indicating that the structures became more compact (Figure 14). *Molecules* **2022**, *27*, x 15 of 21

**Figure 14.** The radius of gyration (Rg) for SRXD complex (black) and CTcD complex (green) during 100 ns simulation time. **Figure 14.** The radius of gyration (Rg) for SRXD complex (black) and CTcD complex (green) during 100 ns simulation time.

The number of hydrogen bond interactions between ligand and receptor combinations (SRXD and CTcD) were displayed against time using a grid search on a 15 × 20 × 27 grid with a rcut = 0.35 value (Figure 15). The number of hydrogen bond interactions between ligand and receptor combinations (SRXD and CTcD) were displayed against time using a grid search on a 15 × 20 × 27 grid with a rcut = 0.35 value (Figure 15).

The hydrogen bonds between SRX and dopamine were at 33 and 1356 atoms, respectively. While they were between 56 and 5109 atoms for the CT complex and dopamine. However, there were 709 donors for both (SRXD and CTcD), 1356 acceptors for SRXD, and 1426 acceptors for CTcD. For SRXD and CTcD, the average number of hydrogen bonds per time was found to be 0.065 and 0.144 out of 480,702 possible.

Overall, these findings suggest that the receptor–protein interaction increased the number of hydrogen bonds by a significant amount in CTcD. As the ligand attached to the receptor, the values of the solvent-accessible surface area (SASA) changed (Figure 16). When the receptor interacts with the ligand, the SASA is lowered, indicating a change in protein structure and a smaller pocket size with increased hydrophobicity.

100 ns simulation time.

grid with a rcut = 0.35 value (Figure 15).

**Figure 14.** The radius of gyration (Rg) for SRXD complex (black) and CTcD complex (green) during

The number of hydrogen bond interactions between ligand and receptor combina-

*Molecules* **2022**, *27*, x 15 of 21

**Figure 15.** Number of average hydrogen bonding interactions between (**Left**) SRXD complex and (**Right**) CTcD complex during 100 ns simulation time. When the receptor interacts with the ligand, the SASA is lowered, indicating a change in protein structure and a smaller pocket size with increased hydrophobicity.

the receptor, the values of the solvent-accessible surface area (SASA) changed (Figure 16).

**Figure 16.** Solvent accessible surface area analysis for the SRXD complex (black) and the CTcD complex (green) during 100 ns simulation time. **Figure 16.** Solvent accessible surface area analysis for the SRXD complex (black) and the CTcD complex (green) during 100 ns simulation time.

#### *3.6. Theoretical Structural Analysis 3.6. Theoretical Structural Analysis*

Density functional theory (DFT) using B-3LYP/6-311G++ (basis set) level of theory and optimized geometry of the CT complexes- [(SRX)(PA}], [(SRX)(DNB), [(SRX)(p-NBA)], [(SRX)(DCQ)], [(SRX)(DBQ)], and [(SRX)(TCNQ)] with atomic coordinates, strainfree lattice constants and ground state minimum energy structure are obtained. The optimized structures of all the CT complexes with the Mulliken numbering scheme are shown in Figure 17. The minimum SCF energy of obtained for [(SRX)(PA}], [(SRX)(DNB), [(SRX)(p-NBA)], [(SRX)(DCQ)], [(SRX)(DBQ)], and [(SRX)(TCNQ)] is −1958.944644 to, Density functional theory (DFT) using B-3LYP/6-311G++ (basis set) level of theory and optimized geometry of the CT complexes- [(SRX)(PA}], [(SRX)(DNB), [(SRX)(p-NBA)], [(SRX)(DCQ)], [(SRX)(DBQ)], and [(SRX)(TCNQ)] with atomic coordinates, strain-free lattice constants and ground state minimum energy structure are obtained. The optimized structures of all the CT complexes with the Mulliken numbering scheme are shown in Figure 17. The minimum SCF energy of obtained for [(SRX)(PA}], [(SRX)(DNB), [(SRX)(p-

−1689.608194, −1673.728419, −2788.736562, −7011.542112, and −1726.964350 a.u in 87, 90, 38, 176, 34, and 91 steps, respectively (Figure 18). Based on the optimized structure, some

extent) were calculated in the gas phase (Table 4). The HOMO–LUMO gap (∆E) for [(SRX)(PA}], [(SRX)(DNB), [(SRX)(p-NBA)], [(SRX)(DCQ)], [(SRX)(DBQ)], and [(SRX)(TCNQ)] was calculated as 2.78, 3.44, 3.31, 2.29, 2.43, and 1.89 eV, respectively. The overall order of the chemical reactivity of the CT complexes on the bases of ∆E is as > [(SRX)(DNB)].

**(a.u.)** 

NBA)], [(SRX)(DCQ)], [(SRX)(DBQ)], and [(SRX)(TCNQ)] is −1958.944644 to, −1689.608194, −1673.728419, −2788.736562, −7011.542112, and −1726.964350 a.u in 87, 90, 38, 176, 34, and 91 steps, respectively (Figure 18). Based on the optimized structure, some molecular parameters (SCF minimum energies, dipole moments, and Electronic spatial extent) were calculated in the gas phase (Table 4). The HOMO–LUMO gap (∆E) for [(SRX)(PA}], [(SRX)(DNB), [(SRX)(p-NBA)], [(SRX)(DCQ)], [(SRX)(DBQ)], and [(SRX)(TCNQ)] was calculated as 2.78, 3.44, 3.31, 2.29, 2.43, and 1.89 eV, respectively. The overall order of the chemical reactivity of the CT complexes on the bases of ∆E is as follows- [(SRX)(TCNQ)] > [(SRX)(DCQ)] > [(SRX)(DBQ)] > [(SRX)(PA}] > [(SRX)(p-NBA)] > [(SRX)(DNB)]. **CT Complex Minimum SCF Energy (Debye) (a.u.)** ∆- **(eV)**  [(SRX)(PA}] −1958.944644 10.500053 33,762.8991 2.7845 [(SRX)(DNB)] −1689.608194 9.644797 20,168.3034 3.4449 [(SRX)(p-NBA)] −1673.728419 11.524028 26,521.9908 3.3189 [(SRX)(DCQ)] −2788.736562 5.693616 19,344.1851 2.3924 [(SRX)(DBQ)] −7011.542112 5.965700 18,542.9710 2.4310 [(SRX)(TCNQ)] −1726.964350 5.607618 35,156.4199 1.8942

**Electronic Spatial Extent**

follows- [(SRX)(TCNQ)] > [(SRX)(DCQ)] > [(SRX)(DBQ)] > [(SRX)(PA}] > [(SRX)(p-NBA)]

*Molecules* **2022**, *27*, x 17 of 21

**Dipole Moment**

**Figure 17.** Optimized structure of (**a**) [(SRX)(PA}], (**b**) [(SRX)(DNB), (**c**) [(SRX)(p-NBA)], (**d**) [(SRX)(DCQ)], (**e**) [(SRX)(DBQ)], and (**f**) [(SRX)(TCNQ)] with Mulliken atom numbering scheme. **Figure 17.** Optimized structure of (**a**) [(SRX)(PA}], (**b**) [(SRX)(DNB), (**c**) [(SRX)(p-NBA)], (**d**) [(SRX)(DCQ)], (**e**) [(SRX)(DBQ)], and (**f**) [(SRX)(TCNQ)] with Mulliken atom numbering scheme.

**4. Conclusions** 

*Molecules* **2022**

**Figure 18.** Optimization step graph for (**a**) [(SRX)(PA}], (**b**) [(SRX)(DNB), (**c**) [(SRX)(p-NBA)], (**d**) [(SRX)(DCQ)], (**e**) [(SRX)(DBQ)], and (**f**) [(SRX)(TCNQ)]**. Figure 18.** Optimization step graph for (**a**) [(SRX)(PA}], (**b**) [(SRX)(DNB), (**c**) [(SRX)(p-NBA)], (**d**) [(SRX)(DCQ)], (**e**) [(SRX)(DBQ)], and (**f**) [(SRX)(TCNQ)].


**Table 4.** Theoretical molecular parameters of the CT complexes obtained through DFT.
