Supporting Information
Development and Validation of Hydrophobic Molecular
Fields Derived from the Quantum Mechanical IEF/PCMMST Solvation Model in 3D-QSAR
Tiziana Ginex,1 Jordi Muñoz-Muriedas,2 Enric Herrero,3 Enric Gibert,3 Pietro
Cozzini,1* and F. Javier Luque4*
1 Dipartimento di Scienze degli Alimenti, University of Parma, Parco Area delle
Scienze 59/A, 43121 Parma, Italy
2 GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1
2NY, United Kingdom
3 Pharmacelera, Jordi Girona 1-3, Campus Nord Universitat Politècnica de Catalunya,
Edific K2M, 08034 Barcelona, Spain
4 Department of Chemical Physics and Institut de Biomedicina (IBUB), Faculty of
Pharmacy, University of Barcelona, Av. Prat de la Riba 171, 08921 Santa Coloma de
Gramenet, Spain
Figure S1. Chemical structures for Dopamine D2/D4 inhibitors (D2/D4 training set).
Figure S2. Chemical structures for Dopamine D2/D4 test set inhibitors (D2: 33-38; D4:
34, 36, 37, 39-41).
Figure S3. Chemical structures of the two main scaffolds present in the set of antifungal
4-aryl-2-chromanones. Chemical structures of compounds (2, 3, 8, 17-19, 20-33)
discussed in the text are shown.
* Het: 2-thienyl, 2-furanyl, 2-pyridinyl or 3-pyridinyl.
Figure S4. Chemical structures of the two main scaffolds for the series of GSK3
the text are shown.
-41, 52, 65 and 67) discussed in
Figure S5. Chemical structures of the three main scaffolds in the set of cruzain
inhibitors. Chemical structures of compounds (12-25) discussed in the text are shown.
Figure S6a. Chemical structures of thermolysin inhibitors (1-20).
Figure S6b. Chemical structures of thermolysin inhibitors (21-48).
Figure S6c. Chemical structures of thermolysin inhibitors (49-74).
a
Thermolysin test set compounds.
Figure S7. Histograms of molecular properties (molecular weight, MW; number of
hydrogen-bond donors/acceptors, HBD/HBA; clogP; and number of rotatable bonds)
for D2/D4 inhibitors.
Figure S8. Histograms of molecular properties (molecular weight, MW; number of
hydrogen-bond donors/acceptors, HBD/HBA; clogP; and number of rotatable bonds)
for 4-aryl-2-chromanones.
Figure S9. Histograms of molecular properties (molecular weight, MW; number of
hydrogen-bond donors/acceptors, HBD/HBA; clogP; and number of rotatable bonds)
for GSK-3 inhibitors.
Figure S10. Histograms of molecular properties (molecular weight, MW; number of
hydrogen-bond donors/acceptors, HBD/HBA; clogP; and number of rotatable bonds)
for cruzain inhibitors.
Figure S11. Histograms of molecular properties (molecular weight, MW; number of
hydrogen-bond donors/acceptors, HBD/HBA; clogP; and number of rotatable bonds)
for thermolysin inhibitors.
Figure S12. Analysis for the MST-derived hydrophobic descriptors (logPele, logPcav,
and logPvW). For the sake of brevity, comparison is limited to sets of positively charged
(D2: A, D), neutral (GSK-3and negatively charged (thermolysin: C, F)
systems.
Figure S13. Comparison of the results obtained from standard CoMFA models (data
taken from refs. 43-46) and the CoMFA analysis in this study for (A) D2, (B) D4, (C) 2aryl-4-chromanones, (D) GSK-3, (E) cruzain and (F) thermolysin systems.
Compounds of the training/test set are shown in blue/red, respectively.
Figure S14. Comparison of the results obtained from standard CoMSIA models (data
taken from refs. 43-46) and the MST-based H2 model for (A) D2, (B) D4, (C) 2-aryl-4chromanones, (D) GSK-3, (E) cruzain and (F) thermolysin systems. Compounds of the
training/test set are shown in blue/red, respectively.
Table S1. Experimental and HyPhar H2 predicted binding constants for Dopamine D2
and D4 training/test set compounds. Values are expressed as pKi.
a
b
Dopamine D2
Number
Exp
HyPhar H2
1
6.66
6.76
2
8.60
8.95
3
8.89
7.88
4
7.37
8.13
5
6.28
6.97
6
7.33
7.19
7
7.68
7.63
8
8.43
7.70
9
8.18
7.90
10
8.92
8.47
11
6.82
7.19
12
7.29
7.17
13
6.10
6.66
14
8.55
8.36
15
6.04
5.89
16
6.80
6.88
17
6.60
6.17
18
5.66
6.59
19
5.84
5.49
20
7.83
7.01
21
7.10
7.35
22
5.84
6.26
a
23
10.3
9.08
24
8.89
8.61
25
7.22
6.77
26
6.07
6.57
27
6.05
6.56
28
5.89
6.44
29
6.40
7.80
30
9.82
10.18
31
6.28
6.78
32
7.19
6.45
33 a
5.65
6.22
a,b
34
8.55
8.03
35 a
7.05
6.91
a,b
36
6.72
7.27
37 a.b
7.71
8.57
a
38
5.89
6.21
39 b
b
40
41 b
Dopamine D2 test set compounds.
Dopamine D4 test set compounds.
Dopamine D4
Exp
HyPhar H2
7.68
7.76
7.46
8.28
8.19
7.89
7.10
8.10
7.68
7.79
7.80
7.82
8.31
7.89
7.89
7.89
7.96
7.81
8.41
7.82
7.64
7.95
9.00
8.44
8.66
8.81
8.48
9.01
8.44
7.82
8.52
8.95
8.28
8.12
8.07
8.14
8.22
8.01
8.96
8.45
9.05
8.42
7.59
8.16
10.3
8.94
8.75
9.04
8.00
7.69
7.66
7.74
7.64
7.87
7.28
7.94
8.25
8.53
9.38
9.72
8.26
7.82
7.72
7.78
8.96
7.96
8.12
8.64
7.94
8.08
9.37
8.58
7.22
8.08
7.36
8.27
Table S2. Experimental and HyPhar H2 predicted inhibitory activities for 4-aryl-2chromanones training/test set compounds.
a
pIC50
Number
Exp
HyPhar H2
1
5.90
5.92
2
6.29
6.22
3
5.14
5.12
4
5.89
5.80
5
5.73
5.72
8
4.66
4.75
9
5.87
5.87
10
5.44
5.48
12
5.18
5.20
13
6.04
6.10
14
5.84
5.61
15
5.84
5.87
16
5.76
6.02
18
5.09
5.25
19
6.22
6.27
20
6.13
5.95
21
5.87
5.74
22
6.01
5.91
24
5.73
5.82
25
5.85
5.65
26
5.36
5.27
27
5.38
5.48
28
5.76
5.74
29
5.49
5.70
31
5.71
5.61
32
5.10
5.11
33
6.23
6.35
6a
5.83
6.08
a
7
5.40
5.71
11 a
5.66
5.46
a
17
4.98
5.13
23 a
6.24
6.26
30 a
5.27
5.21
a
34
5.86
6.15
Molecules used as external test set.
Table S3. Experimental and HyPhar H2 predicted inhibitory activities for GSK-3
training/test set compounds.
pIC50
Number
Exp
HyPhar H2
2
6.67
6.39
4
6.85
6.78
5
6.29
6.31
6
6.41
6.36
7
6.52
6.42
8
6.71
6.65
10
6.98
6.89
11
6.59
6.50
13
6.35
6.52
14
6.81
6.51
15
6.15
6.20
16
6.43
6.45
17
6.59
6.57
18
6.60
6.75
20
6.33
6.33
21
6.63
6.79
23
6.32
6.35
24
6.91
6.83
26
6.82
6.78
28
6.98
7.08
29
7.03
6.82
30
7.23
7.27
31
6.76
6.74
33
7.03
7.04
34
7.09
7.24
35
7.28
7.31
37
6.85
6.98
38
7.70
7.47
39
7.04
6.99
40
7.08
7.06
41
7.15
7.24
42
6.54
6.73
44
6.87
6.99
45
6.71
6.78
47
6.73
6.72
48
6.67
6.77
50
7.13
7.13
a
Molecules used as external test set.
Number
51
52
53
54
55
56
58
59
60
61
63
64
65
67
68
70
71
72
74
1a
3a
9a
12 a
19 a
22 a
25 a
27 a
32 a
36 a
43 a
46 a
49 a
57 a
62 a
66 a
69 a
73 a
Exp
7.55
7.12
7.07
7.59
6.96
6.39
6.96
6.27
6.69
6.82
6.61
6.41
5.58
5.64
6.47
6.88
6.34
6.79
6.16
6.28
6.67
6.94
7.15
5.83
6.39
6.50
6.86
6.83
7.24
6.87
7.10
6.85
6.79
6.28
5.85
6.73
5.85
pIC50
HyPhar H2
7.46
7.26
7.09
7.54
7.01
6.31
6.75
6.47
6.47
6.86
6.50
6.56
5.68
5.65
6.54
6.73
6.40
6.72
6.42
6.29
6.66
6.76
6.95
6.48
6.35
6.46
6.91
6.94
7.13
6.93
7.24
6.94
6.60
6.33
6.03
6.68
6.32
Table S4. Experimental and HyPhar H2 predicted inhibitory activities for cruzain
training/test set compounds.
a
pIC50
Number
Exp
HyPhar H2
1
6.15
6.44
2
6.15
6.49
3
6.10
6.25
4
6.05
6.42
6
6.05
6.22
7
6.05
6.15
8
6.05
6.20
9
5.90
6.25
11
5.80
5.68
12
7.20
7.12
14
7.10
6.67
15
7.00
7.11
16
6.90
6.54
17
6.90
6.56
18
5.95
6.13
19
5.65
5.74
20
7.20
6.80
22
7.60
6.95
23
8.00
7.64
25
7.74
7.97
26
7.74
7.67
27
7.40
7.96
28
7.30
7.03
29
7.20
7.26
30
7.15
7.37
32
6.50
6.23
a
5
6.05
5.95
10 a
5.85
6.21
a
13
7.10
6.62
21 a
6.40
6.88
a
24
7.89
7.82
31 a
6.60
7.23
Molecules used as external test set.
Table S5. Experimental and HyPhar H2 predicted inhibitory activities for Thermolysis
inhibitors training/test set compounds.
N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
a
pKi
Name
Exp HyPhar H2
ace_ohleu_agnh2
2.47
2.38
bzsag
6.12
5.00
c6pltnme
8.82
8.14
c6poltnme
5.84
6.61
ch3coch2co_fagnh2
2.51
2.29
cho_ohleu_agnh2
2.47
2.68
cltzncrys
7.47
7.82
dah50
7.96
8.69
dah51
6.22
5.69
dah52
5.55
5.62
dah53
6.66
7.04
nhohbzmagnh2
6.18
4.97
nhohbzmagoh
6.18
6.73
nhohmalagnh2
2.96
3.15
ohbzmagnh2
3.38
3.30
p_ophe_ome_leunh2 0.52
1.49
paaoh
4.06
4.01
po3_fagnh2
5.59
5.58
ppheoh
4.14
5.42
z_d_apola
4.62
4.60
z_nh_glnhoh
5.57
4.06
zala
6.07
6.42
zapola
5.74
7.03
zfpola
7.35
7.45
zg_d_lnhoh
4.32
4.71
zgg_d_lnhoh
3.60
4.54
zgglnhoh
4.41
3.85
zglnh2
1.68
3.09
zglnhoh
4.89
4.70
zglnmeoh
2.65
2.30
zgly
6.39
5.98
zgpcllzncrys
6.74
7.21
zgpla
7.78
6.48
zgpllzncrys
8.04
6.50
zgpola
4.89
4.93
zgpollzncrys
5.05
5.23
zlpola
6.17
5.03
Molecules used as external test set.
N
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
Name
c6pcltnme
ch3o2s_fagnh2
cbzphe
dah54
dah55
hoch2co_fagnh2
nhohbzmagna
nhohbzmoet
nhohibmagnh2
nhohleu
p_ile_aoh
phosphoramidon
pleunh2
pnhet
r_thiorphan
s02p_fagnh2
s_thiorphan
so3_fagnh2
z_d_lpola
z_nh_glnh2
zfplazncrys
zggnhoh
zgplg a
zgplf a
zgplnh2 a
zgpolg a
zgpolf a
zgpolnh2 a
zgpcla a
zgpclg a
zgpclf a
zgpclnh2 a
ppphe a
plfoh a
zfgnh2 a
zlgnh2 a
zygnh2 a
Exp
7.28
0.52
3.29
5.77
2.42
2.54
6.37
4.70
6.32
3.72
6.44
7.55
4.10
0.52
5.64
5.16
5.74
2.37
4.38
3.42
10.17
3.03
6.57
7.12
6.12
3.64
4.27
3.18
7.73
6.52
7.18
5.85
2.79
7.72
3.46
2.51
3.66
pKi
HyPhar H2
7.39
2.99
2.41
5.33
2.96
2.52
7.18
4.56
4.32
3.10
6.89
7.13
2.96
0.35
4.66
5.85
5.56
3.52
5.83
3.52
9.13
3.64
5.58
5.89
3.83
4.82
5.32
0.03
5.93
6.31
6.50
4.08
2.65
5.84
2.30
2.20
3.47
Table S6. Levels of isocontours (expressed as the PLS coeficients corrected by the
standard deviation) used in the pharmacophoric maps shown in Figures 4, 6, 8, 10 and
11. All values were scaled by a factor of 105.
System
GSK-3
Field
Level
(Figure 4)
CoMFA
HyPhar H2
Electrostatic
+3 / -3
Steric
+225 / -225
logPele
+17 / -17
logPcav
+6 / -6
Cruzain (Figure 6)
CoMFA
HyPhar H2
Electrostatic
+8 / -8
Steric
+165 / -165
logPele
+1.3 / -1.3
logPcav
+8 / -8
Thermolysin (Figure 8)
CoMFA
HyPhar H2
Electrostatic
+30 / -70
Steric
+2000 / -1500
logPele
+300 / -300
logPcav
+30 / -18
Electrostatic
+2.5 / -2.5
Steric
+53 / -53
logPele
+1.8 / -1.8
logPcav
+2.5 / -2.5
Electrostatic
+2.5 / -2.5
Steric
+65 / -65
logPele
+6 / -6
logPcav
+0.7 / -0.7
D2 (Figure 10)
CoMFA
HyPhar H2
D4 (Figure 10)
CoMFA
HyPhar H2
2-aryl-4-chromanones (Figure 11)
CoMFA
Electrostatic
+1.5 / -1.5
HyPhar H2
Steric
+450 / -450
logPele
+4 / -4
logPcav
+7 / -7