# Discovery of new chemotypes of dual 5-HT2A/D2 receptor antagonists with a strategy of drug design methodologies - Supplementary data review2.docx

Figure S1. PCA score plot obtained for 5-HT2A/D2-R antagonists. Cluster 1- tricyclic derivatives of dibenzocycloheptene (clozapine-like compounds) are depicted in dark blue; cluster 2- derivatives of 1,2-benzoisothiazole (ziprasidone-like compounds) are depicted in green, and cluster 3- tetracyclic quinoxaline derivatives (lumateperone-like compounds) are depicted in light blue.

Figure S2. Dominant chemical structures of compounds from cluster 1 used for 3D-QSAR modeling at the physiological pH 7.4.

Figure S3. Dominant chemical structures of compounds from cluster 1 used for 3D-QSAR modeling at the physiological pH 7.4.

Figure S4. Dominant chemical structures of compounds from cluster 2 used for 3D-QSAR modeling at the physiological pH 7.4.

Figure S5. Dominant chemical structures of compounds from cluster 3 used for 3D-QSAR modeling at the physiological pH 7.4.

Figure S6. Conformations of 5-HT2A-R –clozapine ((A)-yellow), 5-HT2A-R –ziprasidone ((E)-blue) and 5-HT2A-R –lumateperone ((I)-purple) complexes after 50 ns long MD simulations; (A) Binding interactions of clozapine in 5-HT2A-R; Plots of: (B) RMSD of 5-HT2A-R backbone, (C) RMSD of ligand and (D) RMSD of residues in the binding site for 5-HT2A-R -clozapine complex; (E) Binding interactions of ziprasidone in 5-HT2A-R; Plots of: (F) RMSD of 5-HT2A-R backbone, (G) RMSD of ligand and (H) RMSD of residues in the binding site for 5-HT2A-R -ziprasidone complex; (I) Binding interactions of lumateperone in 5-HT2A-R; Plots of: (J) RMSD of 5-HT2A-R backbone, (K) RMSD of ligand and (L) RMSD of residues in the binding site for 5-HT2A-R -lumateperone complex. RMSD - root mean square deviation.

Figure S7. Conformations of D2-R –clozapine ((A)-yellow), D2-R –ziprasidone ((E)-blue) and D2-R –lumateperone ((I)-purple) complexes after 50 ns long MD simulations; (A) Binding interactions of clozapine in D2-R; Plots of: (B) RMSD of D2-R backbone, (C) RMSD of ligand and (D) RMSD of residues in the binding site for D2-R -clozapine complex; (E) Binding interactions of ziprasidone in D2-R; Plots of: (F) RMSD of D2-R backbone, (G) RMSD of ligand and (H) RMSD of residues in the binding site for D2-R -ziprasidone complex; (I) Binding interactions of lumateperone in D2-R; Plots of: (J) RMSD of D2-R backbone, (K) RMSD of ligand and (L) RMSD of residues in the binding site for D2-R -lumateperone complex. RMSD - root mean square deviation.

Figure S8. Conformations of H1-R –clozapine ((A)-yellow), H1-R –ziprasidone ((E)-blue) and H1-R –lumateperone ((I)-purple) complexes after 50 ns long MD simulations; (A) Binding interactions of clozapine in H1-R; Plots of: (B) RMSD of H1-R backbone, (C) RMSD of ligand and (D) RMSD of residues in the binding site for H1-R -clozapine complex; (E) Binding interactions of ziprasidone in H1-R; Plots of: (F) RMSD of H1-R backbone, (G) RMSD of ligand and (H) RMSD of residues in the binding site for H1-R -ziprasidone complex; (I) Binding interactions of lumateperone in H1-R; Plots of: (J) RMSD of H1-R backbone, (K) RMSD of ligand and (L) RMSD of residues in the binding site for H1-R -lumateperone complex. RMSD - root mean square deviation.

**Figure S9.** Number of hydrogen bonds in studied systems during the 50 ns molecular dynamics simulations. (A) 5-HT2A-R -clozapine; (B) 5-HT2A-R -ziprasidone; (C) 5-HT2A-R -lumateperone; (D) D2-R -clozapine; (E) D2-R -ziprasidone; (F) D2-R -lumateperone; (G) H1-R –clozapine; (H) H1-R –ziprasidone; (I) H1-R –lumateperone.

**Figure S10.** Solvent accessible surface area (SASA) values for binding sites of studied complexes during the 50 ns molecular dynamics simulations. (A) 5-HT2A-R –clozapine (yellow), 5-HT2A-R –ziprasidone (blue), 5-HT2A-R –lumateperone (purple); (B) D2-R –clozapine (yellow), D2-R –ziprasidone (blue), D2-R –lumateperone (purple); (C) H1-R –clozapine (yellow), H1-R –ziprasidone (blue), H1-R –lumateperone (purple).

Figure S11. PLS coefficients plot with the most important variables for 5-HT2A-R 3D-QSAR model.

Figure S12. PLS coefficients plot with the most important variables for D2-R 3D-QSAR model.

Figure S13. PLS coefficients plot with the most important variables for H1-R 3D-QSAR model.

**3D-QSAR study for 5-HT2A-R**

**Molecular docking study for 5-HT2A-R**

**3D-QSAR study for D2-R**

**Molecular docking study for D2-R**

Figure S14. Alignment of residues in the binding sites of 5-HT2A, D2 and H1 receptors by their position, obtained from GPCRdb. Residues with hydrophobic aromatic properties are colored in green, while those with hydrophobic aliphatic properties are in yellow. Purple represents residues which can form hydrogen bond interactions, while red define residues which are charged negative. Brown characterizes cysteine which can form disulfide bridge.

Figure S15. Applicability domain of the created 5-HT2A-R 3D-QSAR model.

Figure S16. Applicability domain of the created D2-R 3D-QSAR model.

Figure S17. Applicability domain of the created H1-R 3D-QSAR model.

Figure S18. Chemical structures of designed compounds at pH 7.4.

Figure S19. Applicability domain of 5-HT2A-R for the training, test and designed compounds of AutoDock Vina conformers.

Figure S20. Applicability domain of D2-R for the training, test and designed compounds of AutoDock Vina conformers.

Figure S21. Applicability domain of H1-R for the training, test and designed compounds of AutoDock Vina conformers.

Table S1. List of data set compounds from training and test (*) sets for 5-HT2A-R model.

**Table S2**. List of data set compounds from training and test (*) sets for D2-R model.

**Table S3.** List of data set compounds from training and test (*) sets for H1-R model.

Table S4. AutoDock Vina results for 5-HT2A-R data set compounds.

**Table S5.** AutoDock Vina results for D2-R data set compounds.

**Table S6.** AutoDock Vina results for H1-R data set compounds.

Table S7. Results of 3D-QSAR model for 5-HT2A-R.

**Table S8.** Results of 3D-QSAR model for D2-R.

**Table S9.** Results of 3D-QSAR model for H1-R.

**Table S10.** Selected fragments from FBDD screening.

**Table S11.** AD Vina docking scores and predicted pKi values of designed compounds.

**Table S12. **Predicted physico-chemical parameters of the designed compounds.

**Table S13.** Predicted pharmacokinetic properties of the designed compounds.