Molecular Docking and Receptor Specific 3D-QSAR Studies of Acetylcholinesterase Inhibitors

Pran Kishore Deba, Anuradha Sharmaa, Poonam Piplania*, Raghuram Rao Akkinepallyb aPharmaceutical Chemistry Division, University Institute of Pharmaceutical Sciences and Centre of Advanced Study in Pharmaceutical Sciences (UGC-CAS), Panjab University, Chandigarh-14, India; bMedicinal Chemistry Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal-09, India

Supplementary Materials

Table S1 List of crystal structures of AChE and their bound co-crystal ligand reported in PDB

S. No. PDB Source Co-crystal Ligand Resolution Referenc (Å) e 1. 2X8B Homo Fasciculin 2.95 [7a] Sapiens 2. 1B41 Homo Fasciculin-2 2.76 [7b] Sapiens 3. 1EVE Torpedo E2020 (Donepezil) 2.5 [8] Californica 4. 2ACE Torpedo Acetylcholine (Ach) 2.5 [9] Californica 5. 1VOT Torpedo Huperzine A 2.5 [9] Californica 6. 1DX6 Torpedo Galanthamine 2.8 [10] Californica 7. 1ACJ Torpedo Tacrine 2.8 [11] Californica 8. 1DX6 Torpedo Tetraethylene Glycol 2.8 [10] Californica 9. 1DX6 Torpedo N-Acetyl-D-Glucosamine 2.8 [10] Californica 10. 1HBJ Torpedo 1-[3-({[(4-Amino-5-Fluoro-2-Methylquinolin- 2.5 [12] Californica 3-Yl)Methyl]Thio}Methyl)Phenyl]- 2,2,2- Trifluoroethane-1,1-Diol 11. 1HBJ Torpedo 2-(N-Morpholino)-Ethanesulfonic Acid 2.5 [12]

1 Californica 12. 1HBJ Torpedo Tetraethylene Glycol 2.5 [12] Californica 13. 1VXO Torpedo Methylphosphonic Acid Ester Group 2.2 [13] Californica 14. 1VXO Torpedo 2-(Acetylamino)-2-Deoxy-A-D- 2.2 [13] Californica Glucopyranose 15. 1VXO Torpedo N-Acetyl-D-Glucosamine 2.2 [13] Californica 16. 1VXR Torpedo 2-(Acetylamino)-2-Deoxy-A-D- 2.2 [13] Californica Glucopyranose 17. 1VXR Torpedo 2-(N-Morpholino)-Ethanesulfonic Acid 2.2 [13] Californica 18. 1VXR Torpedo O-Ethylmethylphosphonic Acid Ester Group 2.2 [13] Californica 19. 1W4L Torpedo Galanthamine Derivative 2.16 [14] Californica 20. 1W4L Torpedo N-Acetyl-D-Glucosamine 2.16 [14] Californica 21. 1W6R Torpedo (-)-Galanthamine 2.05 [14] Californica 22. 1W6R Torpedo N-Acetyl-D-Glucosamine 2.05 [14] Californica 23. 1W75 Torpedo N-Acetyl-D-Glucosamine 2.4 [14] Californica 24. 1W76 Torpedo (-)-Galanthamine 2.3 [14] Californica 25. 1W76 Torpedo N-Acetyl-D-Glucosamine 2.3 [14] Californica 26. 2CKM Torpedo N,N’-Di-1,2,3,4-Tetrahydroacridin-9- 2.15 [15] Californica Ylheptane-1,7-Diamine 27. 2CKM Torpedo N-Acetyl-D-Glucosamine 2.15 [15] Californica 28. 2CMF Torpedo N,N’-Di-1,2,3,4-Tetrahydroacridin-9- 2.5 [15] Californica Ylpentane-1,5-Diamine 29. 2CMF Torpedo N-Acetyl-D-Glucosamine 2.5 [15] Californica 30. 1ACL Torpedo Decamethonium ion 2.80 [11] Californica 31. 1AMN Torpedo m-(N,N,N-trimethylammonio) 2.80 [16] Californica trifluoroacetophen-one 32. 2ACK Torpedo Edrophonium ion 2.40 [17]

2 Californica

Table S2 Training set (n = 69) and test set (n = 22) of ligands obtained through k-Means clustering

Data Set (n = 91) Serial number of compounds

1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, 14, 16, 17, 18, 19, 20, 22, 23, 25, 26, 27, 29, 31, 32, 33, Training set (n = 69) 34, 35, 36, 38, 39, 40, 42, 43, 44, 45, 46, 48, 49, 50, 52, 53, 54, 56, 58, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 74, 75, 77, 79, 80, 81, 84, 85, 86, 87, 89, 90

Test set (n = 22) 9, 11, 15, 21, 24, 28, 30, 37, 41, 47, 51, 55, 57, 59, 61, 73, 76, 78, 82, 83, 88, 91

3 Table S3 k-Means clustering of ligands (n = 91) using scoring functions

No. of compounds in each Cluster number Serial number of compounds under different clusters cluster

1 16 1, 2, 19, 24, 25, 26, 29, 30, 36, 49, 50, 51, 52, 53, 54, 55

2 13 33, 38, 39, 78, 79, 80, 81, 82, 84, 86, 87, 88, 89

3 14 3, 20, 21, 22, 23, 27, 28, 31, 34, 35, 37, 40, 85, 90

4 24 4, 7, 10, 11, 16, 18, 32, 41, 42, 43, 44, 47, 48, 56, 58, 59, 62, 63, 66, 69, 71, 73, 75, 91

4 5 24 5, 6, 8, 9, 12, 13, 14, 15, 17, 45, 46, 57, 60, 61, 64, 65, 67, 68, 70, 72, 74, 76, 77, 83

Table S4 RMSD of top 3 configurations obtained through docking of co-crystal E2020

into the binding site of crystal structure of acetylcholinesterase (PDB ID: 1EVE)

RMSD heavy atoms (Å) Configuration GOLD LigandFit GLIDE

1 0.52 0.42 0.34

2 0.60 0.45 0.32

3 0.62 0.52 0.37

5 Table S5 Correlations of individual scoring functions with the experimental pIC50 values

S. No. Scoring functions Correlation coefficient (r2) 1 PMF 0.012 2 -PLP1 0.129 3 -PLP2 0.131 4 Jain 0.051 5 LigScore1 dreiding 0.070 6 LigScore2 dreiding 0.036 7 Dock score 0.243 8 Glide score 0.083 9 Gold score 0.371 10 Chem score 0.028

6 11 ASP score 0.182

Table S6 Correlations of individual scoring function descriptors with the experimental pIC50 values

Scoring function Correlation Scoring function Correlation S. No. S. No. descriptors coefficient (r2) descriptors coefficient (r2)

1 S(hb_ext) 0.148 13 S(Map) 0.058 2 S(vdw_ext) 0.084 14 ASP_DE(clash) 0.021 3 S(hb_int) 0.000 15 ASP_DE(int) 0.000 4 S(int) 0.020 16 Hbond 0.027 5 DG 0.057 17 vdW 0.179 6 S(hbond) 0.045 18 Coul 0.133

7 7 S(metal) 0.000 19 Emodel 0.023 8 S(lipo) 0.048 20 CvdW 0.023 9 H(rot) 0.077 21 Intern 0.004 10 DE(clash) 0.037 22 Electro 0.003 11 DE(int) 0.018 23 PhobEn 0.002 12 ASP 0.058 24 PhobEnHB 0.023

Table S7 Correlations of individual embrace descriptors with the experimental pIC50 values

S. Correlation S. Correlation Embrace descriptors Embrace descriptors No. coefficient (r2) No. coefficient (r2) Total energy without 1 0.002 4 Electrostatic energy 0.002 constraints 2 Valence energy 0.314 5 Solvation energy 0.000 3 vdW energy 0.433 6 Constraint energy 0.000

8 Table S8 Correlations of individual ADME descriptors with the experimental pIC50 values

ADME Correlation Correlation S. No. S. No. ADME descriptors descriptors coefficient (r2) coefficient (r2) 1 Stars 0.003 26 QPlogPo/w 0.022 2 Amine 0.006 27 QPlogS 0.048 3 Amidine 0.000 28 CIQPlogS 0.060 4 Acid 0.000 29 QPlogHERG 0.000 5 Amide 0.018 30 QPPCaco 0.040 6 Rotor 0.015 31 QPlogBB 0.065 7 rtvFG 0.003 32 QPPMDCK 0.045 8 CNS 0.095 33 QPlogKp 0.001 9 mol_MW 0.053 34 IP(ev) 0.000 10 Dipole 0.000 35 EA(eV) 0.000 11 SASA 0.026 36 metab 0.078

9 12 FOSA 0.033 37 QPlogKhsa 0.019 Human oral 13 FISA 0.204 38 0.059 absorption Percent human oral 14 PISA 0.012 39 0.003 absorption 15 WPSA 0.288 40 SAfluorine 0.002 16 Volume 0.031 41 SAamideO 0.009 17 donorHB 0.240 42 PSA 0.051 18 accptHB 0.002 43 NandO 0.038 19 dip^2/V 0.000 44 Rule Of five 0.060 ACxDN^.5/S 20 0.034 45 Rule Of three 0.103 A 21 Glob 0.028 46 ringatoms 0.085 22 QPpolrz 0.028 47 in34 0.000 23 QPlogPC16 0.030 48 In56 0.087 24 QPlogPoct 0.085 49 noncon 0.321 25 QPlogPw 0.097 50 nonHatm 0.040

Table S9 Correlation of experimental and predicted acetylcholinesterase inhibitory activity along with their

residual values using Model 1-4 [M1-M4]

Pred_pIC50 (nM) Residual Lig. Exp_pIC50 No. (nM) M1 M2 M3 M4 M1 M2 M3 M4

1 8.26 8.22 8.52 8.17 7.70 0.04 -0.26 0.09 0.56

2 9.30 9.93 8.46 8.47 8.52 -0.63 0.84 0.84 0.79

3 9.00 9.27 9.88 8.19 8.48 -0.27 -0.88 0.81 0.52

4 6.46 5.61 5.33 6.08 6.61 0.85 0.72 0.37 -0.16

5 6.91 6.91 6.54 6.41 7.34 0.00 0.38 0.51 -0.43

6 6.71 6.44 7.03 5.96 7.52 0.27 -0.31 0.75 -0.81

10 7 6.65 6.74 7.03 6.14 6.19 -0.09 -0.39 0.51 0.46

8 6.47 7.04 6.38 6.17 6.90 -0.57 0.09 0.31 -0.43 ts9 6.71 6.18 7.23 5.97 7.30 0.54 -0.51 0.75 -0.58

10 6.51 6.89 7.28 6.23 7.09 -0.38 -0.77 0.28 -0.58 ts11 6.77 6.92 6.49 6.17 7.08 -0.15 0.28 0.60 -0.31

12 7.15 7.23 6.54 6.88 7.21 -0.08 0.61 0.27 -0.07

13 6.63 6.49 6.64 6.64 6.59 0.14 -0.01 -0.01 0.04

14 7.24 7.02 7.38 6.71 7.08 0.21 -0.14 0.53 0.15 ts15 6.98 6.99 6.91 6.55 7.18 -0.01 0.06 0.43 -0.20

16 7.35 7.62 7.51 7.76 7.08 -0.28 -0.16 -0.42 0.26

17 6.80 6.43 6.87 7.07 7.31 0.37 -0.07 -0.27 -0.51

18 6.65 7.57 6.17 6.42 6.29 -0.91 0.48 0.24 0.36

19 8.39 8.93 7.70 8.62 8.55 -0.53 0.69 -0.23 -0.16

20 9.05 8.56 8.71 9.05 10.08 0.49 0.35 0.00 -1.03 ts21 9.17 9.29 9.05 8.44 8.64 -0.12 0.13 0.74 0.53

22 9.57 9.13 8.74 9.27 9.47 0.44 0.83 0.30 0.099

23 8.29 8.33 7.45 8.41 8.01 -0.04 0.84 -0.13 0.28 ts24 8.67 8.69 7.79 8.95 9.43 -0.02 0.87 -0.28 -0.77

25 8.59 8.5 8.58 8.78 8.03 0.083 0.000 -0.19 0.55

26 8.97 8.71 8.85 8.53 9.37 0.26 0.12 0.44 -0.39

27 7.94 7.74 7.99 8.14 8.65 0.19 -0.05 -0.21 -0.71 ts28 8.67 8.44 9.54 8.13 8.35 0.23 -0.88 0.54 0.31

29 8.78 8.99 9.30 7.91 8.25 -0.20 -0.51 0.87 0.53 ts30 8.81 8.99 9.77 8.17 8.32 -0.17 -0.95 0.64 0.49

31 8.59 7.98 9.44 8.55 8.29 0.61 -0.85 0.04 0.30

32 7.67 7.38 7.83 7.76 8.30 0.29 -0.17 -0.09 -0.63

33 4.49 4.84 7.44 5.49 3.28 -0.35 -2.95 -1.00 1.21

34 4.76 4.64 5.32 5.74 4.34 0.12 -0.56 -0.98 0.41

35 4.39 5.27 4.47 4.7 4.11 -0.87 -0.08 -0.31 0.28

36 3.90 4.27 3.60 4.79 4.26 -0.38 0.30 -0.89 -0.36

11 ts37 4.98 4.66 5.73 4.87 4.17 0.32 -0.75 0.11 0.82

38 3.90 4.59 4.53 3.66 4.19 -0.69 -0.64 0.24 -0.30

39 3.55 3.70 4.10 2.96 4.19 -0.15 -0.55 0.59 -0.64

40 3.75 4.27 3.10 4.41 4.10 -0.52 0.63 -0.66 -0.35 ts41 5.52 5.94 5.81 6.3 4.72 -0.42 -0.29 -0.78 0.80

42 7.52 7.75 7.25 7.72 7.34 -0.22 0.27 -0.20 0.18

43 7.76 7.24 7.86 8.57 7.46 0.52 -0.10 -0.81 0.30

44 8.09 8.38 8.36 8.96 8.01 -0.29 -0.27 -0.86 0.08

45 5.73 5.81 6.42 5.25 6.49 -0.09 -0.69 0.48 -0.76

46 7.69 7.98 7.90 8.62 7.29 -0.28 -0.21 -0.93 0.40 ts47 6.38 6.02 7.30 7.15 7.03 0.36 -0.92 -0.77 -0.66

48 6.41 6.95 7.06 6.76 7.13 -0.54 -0.65 -0.35 -0.73

49 9.30 9.08 9.88 8.51 8.49 0.22 -0.58 0.79 0.81

50 10.00 10.55 9.31 9.23 9.30 -0.55 0.69 0.77 0.70 ts51 9.06 9.02 9.01 8.57 9.58 0.043 0.05 0.49 -0.52

52 11.10 10.85 11.24 10.36 10.97 0.25 -0.15 0.74 0.13

53 9.19 8.85 8.45 8.59 8.37 0.34 0.73 0.60 0.82

54 10.40 10.28 10.77 10.4 10.84 0.12 -0.38 0.00 -0.44 ts55 9.35 9.24 10.23 8.62 8.93 0.10 -0.88 0.73 0.41

56 7.00 6.57 6.49 6.34 7.30 0.43 0.51 0.66 -0.30 ts57 7.70 7.81 6.83 7.05 7.26 -0.11 0.87 0.65 0.44

58 7.55 7.25 7.21 8.26 7.03 0.30 0.34 -0.70 0.53 ts59 7.03 7.35 7.07 6.89 6.75 -0.32 -0.04 0.14 0.27

60 8.00 7.87 7.38 8.66 7.61 0.13 0.62 -0.66 0.39 ts61 6.12 6.49 6.29 6.02 6.53 -0.37 -0.17 0.10 -0.41

62 7.57 7.41 6.83 8.2 6.95 0.16 0.74 -0.63 0.62

63 7.09 7.31 6.55 7.79 6.69 -0.22 0.53 -0.70 0.40

64 7.89 7.49 7.12 8.09 7.56 0.39 0.77 -0.20 0.32

65 5.41 5.49 6.25 5.94 5.82 -0.08 -0.83 -0.53 -0.40

66 6.31 5.78 6.01 6.49 6.92 0.54 0.30 -0.17 -0.60

12 67 7.44 6.70 6.93 6.57 7.05 0.45 0.52 0.87 0.39

68 5.17 5.02 5.43 7.72 6.03 0.15 -0.26 -2.55 -0.86

69 5.00 5.76 5.45 4.63 5.71 -0.76 -0.45 0.37 -0.70

70 5.26 5.65 6.06 5.82 5.50 -0.39 -0.80 -0.56 -0.24

71 7.25 7.63 6.94 6.67 6.95 -0.38 0.32 0.58 0.30

72 6.85 6.55 6.65 6.56 6.10 0.30 0.20 0.29 0.75

ts73 6.21 6.89 6.58 6.4 6.82 -0.68 -0.37 -0.18 -0.61

74 7.42 6.83 7.05 7.57 6.89 0.59 0.37 -0.15 0.53

75 5.62 6.14 6.18 6.36 6.23 -0.52 -0.56 -0.74 -0.61

ts76 7.01 7.47 6.97 6.46 6.23 -0.46 0.05 0.55 0.79

77 5.46 4.97 6.02 5.72 5.92 0.50 -0.56 -0.25 -0.45

ts78 7.59 7.13 8.70 7.25 6.74 0.46 -1.11 0.34 0.85

79 5.38 5.32 5.96 4.93 5.66 0.06 -0.58 0.46 -0.28

80 5.26 4.82 5.57 5.32 5.38 0.44 -0.31 -0.06 -0.12

81 5.07 4.78 5.16 5.89 5.55 0.29 -0.1 -0.82 -0.48

ts82 8.32 7.77 8.45 8.12 7.76 0.54 -0.13 0.20 0.55

ts83 7.16 7.70 7.48 7.1 6.23 -0.55 -0.32 0.06 0.93

84 7.80 7.54 7.47 7.91 7.71 0.26 0.33 -0.11 0.09

85 8.85 9.22 7.78 8.81 9.10 -0.37 1.07 0.03 -0.25

86 7.14 6.81 6.90 7.74 6.55 0.33 0.22 -0.60 0.59

87 7.85 7.40 7.80 7.36 8.64 0.45 0.06 0.49 -0.79

ts88 8.11 8.02 8.35 8.53 8.58 0.09 -0.23 -0.42 -0.46

89 9.43 9.81 9.14 9.57 9.71 -0.37 0.29 -0.14 -0.28

90 7.27 6.84 6.78 6.93 6.71 0.43 0.49 0.34 0.56

ts91 5.70 6.20 6.57 5.18 6.44 -0.50 -0.87 0.51 -0.74

*Exp: Experimental, Pred: Predicted, M1: Scoring functions, M2: Scoring function descriptors, M3: Embrace descriptors, M4: ADME descriptors, ts: Test set, pIC50 = -logIC50