A QM protein–ligand investigation of antipsychotic drugs with the dopamine D2 Receptor (D2R)

Figures & data

Figure 1. 2D protonated structures of studied drugs at biological pH of 7.4.

Figure 2. 3D schematic view of the inactive form of D2R in complex with risperidone, which was embedded in the membrane bilayer. Water and ion atoms were rendered by solvation surface and vdW models of VMD, respectively.

Figure 3. 3D structures of the compounds and their surfaces at the binding site of D2R. The amino acids interacting with the drugs are shown.

Table 1. Comparison of calculated ligand binding energies with the experimental results.

Ligand-Asp114 complex	Interaction energy* (kcal/mol)	Interaction energy** (kcal/mol)	Experimental binding energies (kcal/mol)
Risperidone-Asp114	−19.4	−23.4	−11.8
Ziprasidone-Asp114	−22.9	−23.4	−11.6
Aripiprazole-Asp114	−13.6	−25.0	−11.4
Clozapine-Asp114	−24.0	−12.9	−9.7
Olanzapine-Asp114	−22.5	−14.8	−9.9
Quetiapine-Asp114	−14.4	−19.9	−10.6

* Inital positions of atoms were taken from the docking simulations.

** Inital positions of atoms were taken from the MD simulations.

Figure 4. Calculated interaction energies between the drugs and Asp114 using representative structures obtained from the docking and MD simulations. The experimental binding affinities between the drugs and D2R are also given to show more clearly the role of Asp114 in the active site.

Figure 5. 3D structures of drug-Asp114 complexes.

Note: The dotted line indicates the H-bonding.

Table 2. Desolvation, deformation, and binding energies and ligand affinities.

Ligand	Desolvation energy* (kcal/mol)	Deformation energy* (kcal/mol)	Protein–ligand binding energy* kcal/mol	Ligand binding affinity* kcal/mol	Ligand binding affinity** (kcal/mol)	Experimental binding energies (kcal/mol)
Risperidone	53.6	28.3	−132.0	−50.1	−11.0	−11.8
Ziprasidone	59.4	23.1	−166.2	−83.6	−15.1	−11.6
Aripiprazole	63.6	23.4	−152.5	−65.5	−7.9	−11.4
Clozapine	56.6	24.4	−153.4	−72.5	−14.6	−9.7
Olanzapine	55.8	19.8	−149.9	−74.4	−11.8	−9.9
Quetiapine	54.9	35.2	−168.1	−77.9	−7.9	−10.6

* Inital positions of atoms were taken from the docking simulations.

** Inital positions of atoms were taken from the MD simulations.

Figure 6. Interaction energies between the drugs and the active site amino acids except Asp114.