Electronic Supplementary Material (ESI) for Environmental Science: Processes & Impacts.
This journal is © The Royal Society of Chemistry 2017
Supporting Information for:
Predicting the phospholipophilicity of monoprotic
positively charged amines
S.T.J. Droge*a, J.L.M Hermens a, S. Gutsell b, J. Rabone b, G. Hodgesb
a
Institute for Risk Assessment Sciences, Utrecht University, The Netherlands
Safety and Environmental Assurance Centre, Unilever, Sharnbrook, Bedford,
United Kingdom.
b
*
Corresponding author, [email protected]
SI-Tables: 3
SI-Figures: 3
Pages: 10
Supporting information Droge et al. 2016
Table S1. Suppliers and properties of tested amines.
#
Compound
Supplier
purity
Detection
CAS
Use
halogenated/nonpolar amines
1
R-(-) deprenyl HCl
Sigma
>98%
UV
14611-52-0
Antidepressant
2
4-fluoroaniline (f.b.)
Sigma
99%
UV
371-40-4
(Model structure)
3
3-chloroaniline (f.b.)
Sigma
99%
UV
108-42-9
(Model structure)
4
4-chlorobenzylamine (f.b.)
Alfa Aesa
97%
UV
104-86-9
(Model structure)
5
3,4-dichlorobenzylamine (f.b.)
Fluorochem Ltd
98%
UV
102-49-8
(Model structure)
6
sertraline HCl
Sigma
98%
UV
79559-97-0
Antidepressant
simple monopolar amines
7
diphenhydramine HCl
Sigma
>98%
UV
147-24-0
Antidepressant
8
tamoxifen (f.b.)
Sigma
>99%
LC-MS/MS
10540-29-1
SERM
9
fluoxetine HCl
Ehrenstorfer
99%
UV
54910-89-3
Antidepressant
10
duloxetine HCl
Eur.Ph.Ref.
CRS
LC-MS/MS
136434-34-9
Antidepressant
11
N-Benzylaminoacetaldehydediethylacetal (f.b.)
Alfa Aesar
98%
UV
61190-10-1
(Model structure)
12
escitalopram oxalate
Sigma
>98%
LC-MS/MS
219861-08-2
Antidepressant
13
spiroxamine (f.b.)
Sigma
98.8%
LC-MS/MS
118134-30-8
Pesticide
14
MDMA HCl
Duchefa
99.7
UV
42542-10-9
Illicit drug
15
3-dimethylamino-propiophenone HCl
Alfa Aesar
99%
UV
879-72-1
(Model structure)
16
bupropion HCl
Sigma
>98%
UV
31677-93-7
Antidepressant
17
ketamine HCl
Sigma
UV
1867-66-9
Anaesthetic
18
ethyl3-(benzylamino)-propanoate f.b.
Alfa Aesar
96%
UV
23583-21-3
(Model structure)
19
butyrylcholine Cl
Sigma
>98%
UV
2963-78-2
(Model structure)
20
S-Butyrylthiocholine I
Fluka
>99%
UV
1866-16-6
(Model structure)
21
valethamate Br
Alfa Aesar
99%
UV
90-22-2
Spasmolytic
22
cocaine HCl
Spruyt hillen
UV
50-36-2
Illicit drug
simple bipolar amines
23
N-ethanolbenzylamine (f.b.)
Alfa Aesar
96%
UV
104-63-2
(Model structure)
24
methylephedrine (f.b.)
Alfa Aesar
98+%
UV
552-79-4
(Model structure)
25
benzyldimethylhydroxyethylamm. Cl
Sigma
≥97%
UV
7221-40-1
(Model structure)
26
2,2'-(benzylimino)-diethanol (f.b.)
Sigma
CPR>99%
UV
101-32-6
(Model structure)
27
dopamine HCl
Sigma
+98%
UV
62-31-7
Stimulant
28
albuterol sulfate
Sigma
Ph.std.
UV
51022-70-9
Bronchodilator
29
tramadol HCl
Sigma
>99%
UV
27203-92-5
Analgesic
30
alprenolol HCl
Sigma
>98%
UV
13655-52-2
Beta-blocker
31
nadolol (f.b.)
Ehrenstorfer
99.1%
UV
42200-33-9
Beta-blocker
32
metoprolol tartrate
Sigma
>98%
UV
37350-58-6
Beta-blocker
33
propranolol HCl
Promochem
99%
UV
525-66-6
Beta-blocker
34
atropine (f.b.)
Fluka
>95%
UV
51-55-8
Anticholinergic
35
scopolamine HCl
Fluka
99%
UV
51-34-3
Anticholinergic
simple amines with polar N groups
36
procaine HCl
Ehrenstorfer
99.3%
UV
59-46-1
Anaesthetic
37
4-amino-2-methylquinoline (f.b.)
Alfa Aesar
98%
UV
6628-04-2
(Model structure)
38
ropivacaine HCl
Molekula
UV
84057-95-4
Anaesthetic
39
bupivacaine HCl
Fluka
>99%
UV
2180-92-9
Anaesthetic
40
lidocaine (f.b.)
Sigma
>99%
UV
137-58-6
Anaesthetic
41
prilocaine HCl
Sigma
≥98%
UV
721-50-6
Anaesthetic
42
1-benzyl-3-acetamidopyrrolidine (f.b.)
Alfa Aesar
98%
UV
114636-30-5
(Model structure)
43
propamocarb HCl
Ehrenstorfer
99%
LC-MS/MS
24579-73-5
Pesticide
44
neostigmine Br
Sigma
>98%
UV
114-80-7
ACh inhibitor
45
pyridostigmine Br
Sigma
>98%
UV
101-26-8
Ch inhibitor
46
4-carbamoyl-1-pentylpyridinium Br
Sigma
CPR
UV
X-S400483-1EA
(Model structure)
47
4-carbamoyl-1-octylpyridinium Br
Sigma
CPR
UV
X-S421189-1EA
(Model structure)
S2
Supporting information Droge et al. 2016
#
Compound
Supplier
purity
Detection
CAS
Use
48
atenolol (f.b.)
Sigma
99%
UV
56715-13-0
Beta-blocker
49
tryptamine HCl
Sigma
99%
UV
61-54-1
(Model structure)
50
serotonin HCl
Alfa Aesar
99%
UV
50-67-9
(Model structure)
51
benzimidazole (f.b.)
Alfa Aesar
99%
UV
51-17-2
Fungicide
52
thiabendazole (f.b.)
Ehrenstorfer
UV
148-79-8
Fungicide
53
pindolol (f.b.)
Sigma
>98%
UV
13523-86-9
Beta-blocker
54
(S)-(-)nicotine (f.b.)
Alfa Aesar
99%
UV
54-11-5
Opioid
55
clonidine HCl
Fluka
An.std.
UV
4205-90-7
Antihypertensive
56
clotrimazole (f.b.)
Sigma
99.3%
UV
23593-75-1
Fungicide
57
timolol maleate
Ehrenstorfer
99%
LC-MS/MS
26921-17-5
Beta-blocker
58
1,3-diphenylguanidine (f.b.)
Alfa Aesar
99+%
UV
102-06-7
(Model structure)
59
sotalol HCl
Ehrenstorfer
98.5%
UV
959-24-0
Beta-blocker
60
S-sulpiride (f.b.)
Ehrenstorfer
98%
UV
23672-07-3
Antipsychotic
polyaromatic amines
61
morphine sulfate
Spruyt hillen
>98%
UV
6211-15-0
Analgesic
62
naloxone HCl
Alfa Aesar
98%
UV
357-08-4
Opioid antagonist
63
strychnine (f.b.)
Sigma
>98%
UV
57-24-9
Pesticide
64
harmine (f.b.)
Sigma
98%
UV
442-51-3
CNS stimulant
65
harmaline (f.b.)
Sigma
99.2
UV
304-21-2
CNS stimulant
66
promazine HCl
Sigma
99.9%
UV
58-40-2
Antidepressant
67
chlorpromazine HCl
Sigma
>98%
UV
50-53-3
Antidepressant
68
triflupromazine HCl
Sigma
99.7%
UV
146-54-3
Antidepressant
69
doxepin HCl
Alfa Aesar
99.2%
UV
1229-29-4
Antidepressant
70
difenzoquat hemisulfate
Ehrenstorfer
UV
43222-48-6
Pesticide
complex amines (≥ 4 polar groups, and/or large rings, and/or Mw > 400 )
71
(±)-verapamil HCl
Sigma
98%
UV
52-53-9
Ca -channel bl.
72
trimethoprim (f.b.)
Ehrenstorfer
99.5%
UV
738-70-5
Antibiotic
73
loperamide HCl
Sigma
99.9%
UV
34552-83-5
Antiperistaltic
74
ketanserin tartrate
Janssen
>97%
UV
83846-83-7
Antihypertensive
75
amlodipine (f.b.)
Alfa Aesar
97%
UV
88150-42-9
Ca-channel bl.
76
nicardipine HCl
Alfa Aesar
98+%
UV
54527-84-3
Ca-channel bl.
77
acebutolol HCl
Sigma
An.std.
UV
34381-68-5
Beta-blocker
78
lincomycin HCl
Riedel deHaen
103%
UV
7179-49-9
Antibiotic
79
diltiazem ((+)-cis-) HCl
Sigma
>99%
UV
33286-22-5
Ca-channel bl.
80
amiodarone (f.b.)
Sigma
>98%
UV
19774-82-4
Antiarrhythmic
81
ergocornine
Sigma
≥95%
LC-MS/MS
564-36-3
Mycotoxin
82
nefopam HCl
Sigma
>98%
UV
23327-57-3
Analgesic
83
tiamulin fumarate
Riedel de Haen
99.9%
UV
55297-96-6
Antibiotic
84
clarithromycin (f.b.)
Sigma
>98%
LC-MS/MS
81103-11-9
Macrolide
85
erythromycin A (<12% B) (f.b.)
Sigma
>85%
LC-MS/MS
114-078
Macrolide
86
tylosin hemitartrate
Ehrenstorfer
91.4%
LC-MS/MS
1401-69-0
Antibiotic
S3
Supporting information Droge et al. 2016
Table S2. Uncorrected and corrected LogKIAM and LogKDMPC values
#
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
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Name
halogenated/nonpolar amines
deprenyl
4-fluoroaniline
3-chloroaniline
4-chlorobenzylamine
3,4-dichlorobenzylamine
sertraline
simple monopolar amines
diphenhydramine
tamoxifen
fluoxetine
duloxetine
escitalopram
N-benzylaminoacetaldehydediethylacetal
spiroxamine
MDMA
3-dimethylamino-propiophenone
bupropion
ketamine
ethyl-3-(benzylamino)propanoate
butyrylcholine
butyrylthiocholine
valethamate
cocaine
simple dipolar amines
N-ethanolbenzylamine
methylephedrine
benzyldimethylhydroxyethylamm.
2,2'-(benzylimino)-diethanol
dopamine
albuterol
tramadol
alprenolol
nadolol
metoprolol
propranolol
atropine
scopolamine
simple amines with polar N groups
procaine
4-amino-2-methylquinoline
ropivacaine
bupivacaine
lidocaine
prilocaine
1-benzyl-3-acetamidopyrrolidine
propamocarb
neostigmine
pyridostigmine
4-carbamoyl-1-pentylpyridinium
4-carbamoyl-1-octylpyridinium
atenolol
tryptamine
serotonin
benzimidazole
thiabendazole
pindolol
nicotine
clonidine
clotrimazole
timolol
1,3-diphenylguanidine
sotalol
sulpiride
amine
type
logKIAM
pH5.0 d
uncorrected
logKIAM
pH5.0 d
δIAM-SSLM
corrected
logKDMPC d
COSMO
uncorrected
logKDMPC d
TUHH
uncorrected
logKDMPC
COSMO-TUHH
difference
3°
1°
1°
1°
1°
2°
1.97
1.05
1.97
1.66
2.24
4.32
1.94
1.83
2.75
2.44
3.02
4.79
1.05
1.50
1.87
2.07
2.61
3.11
1.48
2.01
2.34
2.53
3.06
3.47
0.4
0.5
0.5
0.5
0.4
0.4
3°
3°
2°
2°
3°
2.88
6.51
4.28
3.93
3.28
1.85
2.85
6.48
4.75
4.40
3.25
2.32
2.86
4.91
3.67
3.52
1.17
1.86
3.28
5.29
4.10
3.93
1.53
2.16
0.4
0.4
0.4
0.4
0.4
0.3
2°
3°
2°
3°
2°
2°
2°
4°
4°
4°
3°
3.30
1.74
1.33
2.42
1.88
1.27
0.66
1.13
3.06
2.10
3.27
2.21
1.30
2.89
2.35
1.74
0.55
1.02
2.95
2.07
3.02
1.19
0.45
1.69
0.93
1.22
-0.02
0.85
2.34
1.31
3.23
1.63
0.83
2.00
1.23
1.60
0.41
1.23
2.65
1.77
0.2
0.4
0.4
0.3
0.3
0.4
0.4
0.4
0.3
0.5
2°
3°
4°
3°
1°
2°
3°
2°
2°
2°
2°
3°
3°
0.97
1.35
1.00
1.01
0.96
1.23
2.01
2.79
1.88
2.06
3.12
1.95
1.42
1.44
1.32
0.89
0.98
1.74
1.70
1.98
3.26
2.35
2.53
3.59
1.92
1.39
0.93
1.00
0.51
0.50
1.99
1.33
1.48
2.56
1.30
2.13
2.66
0.65
0.84
1.42
1.44
0.90
0.99
2.64
1.83
1.76
3.00
1.74
2.57
3.11
1.14
1.39
0.5
0.4
0.4
0.5
0.6
0.5
0.3
0.4
0.4
0.4
0.4
0.5
0.5
3°
3°
3°
3°
3°
2°
3°
3°
4°
4°
4°
4°
2°
1°
1°
3°
3°
2°
3°
3°
3°
2°
2°
2°
3°
1.57
2.04
2.15
2.45
1.66
1.78
1.27
0.95
1.19
0.59
1.12
2.52
1.26
1.91
1.59
1.22
2.28
2.11
0.96
1.71
4.10
1.98
2.05
1.33
1.64
1.54
2.01
2.12
2.42
1.63
2.25
1.24
0.92
1.08
0.48
1.01
2.41
1.73
2.69
2.37
1.19
2.25
2.58
0.93
1.68
4.07
2.45
2.52
1.80
1.61
0.67
0.17
1.37
1.82
1.13
1.93
-0.17
0.37
0.09
-0.40
0.41
2.10
2.12
1.96
1.76
0.46
0.43
1.61
-0.72
0.91
3.16
1.44
1.79
0.66
0.11
0.99
0.67
1.74
2.14
1.58
2.34
0.23
0.70
0.45
-0.07
0.75
2.40
0.70
2.50
2.42
0.96
0.94
2.11
-0.26
1.36
3.33
1.89
2.17
1.22
0.26
0.3
0.5
0.4
0.3
0.4
0.4
0.4
0.3
0.4
0.3
0.3
0.3
0.5
0.5
0.7
0.5
0.5
0.5
0.5
0.5
0.2
0.5
0.4
0.6
0.2
S4
logKDMPC
TUHH
corrected
+0.43
1.91
2.44
2.77
2.96
3.49
3.90
+0.43
3.71
5.72
4.53
4.36
1.96
2.59
3.66
2.06
1.26
2.43
1.66
2.03
0.84
1.66
3.08
2.20
+0.09
1.51
1.53
0.99
1.08
2.73
1.92
1.85
3.09
1.83
2.66
3.20
1.23
1.48
+0.54
1.53
1.21
2.28
2.68
2.12
2.88
0.77
1.24
0.99
0.47
1.29
2.94
1.24
3.04
2.96
1.50
1.48
2.65
0.28
1.90
3.87
2.43
2.71
1.76
0.80
Supporting information Droge et al. 2016
#
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
name
amine
type
logKIAM
pH5.0 d
uncorrected
logKIAM
pH5.0 d
δIAM-SSLM
corrected
polyaromatic amines
morphine
3°
1.29
1.26
naloxone
3°
1.63
1.60
strychnine
3°
2.28
2.25
harmine
3°
3.08
3.05
harmaline
3°
2.78
2.75
promazine
3°
3.87
3.84
chlorpromazine
3°
4.34
4.31
triflupromazine
3°
4.58
4.55
doxepin
3°
3.31
3.28
difenzoquat
4°
2.56
2.45
complex amines (≥ 4 polar groups, and/or large rings, and/or Mw > 400 )
verapamil
3°
4.08
4.05
trimethoprim
3°
2.14
2.11
loperamide
3°
4.44
4.41
ketanserin
3°
3.19
3.16
amlodipine
1°
4.15
4.93
nicardipine
3°
3.89
3.86
acebutolol
2°
2.40
2.87
lincomycin
3°
1.28
1.25
diltiazem
3°
3.26
3.23
amiodarone
3°
4.52
6.48
ergocornine
3°
4.30
4.27
nefopam
3°
2.52
2.49
tiamulin
3°
0.99
0.96
clarithromycin
3°
3.70
3.67
erythromycin
3°
3.38
3.35
tylosine
3°
3.40
3.37
S5
logKDMPC d
COSMO
uncorrected
logKDMPC d
TUHH
uncorrected
logKDMPC
COSMO-TUHH
difference
0.09
0.75
0.00
1.08
0.86
2.37
2.82
3.05
2.32
1.55
0.69
1.22
0.51
1.48
1.21
2.77
3.21
3.45
2.73
1.67
0.2
0.6
0.5
0.5
0.4
0.4
0.4
0.4
0.4
0.4
0.63 $
0.97
4.21
1.63
3.93
2.70
2.16
1.72
1.89
5.50
1.46
1.55
1.82
2.90
3.46
1.99
1.08 $
1.51
4.23
1.92
4.44
3.0
2.62
2.06
2.24
5.68
2.03
1.91
2.01
3.3
3.86
2.48
0.5
0.5
0.0
0.3
0.5
0.3
0.5
0.3
0.4
0.2
0.6
0.4
0.2
0.4
0.4
0.5
logKDMPC
COSMOTUHH
corrected
+0.76
1.45
1.98
1.27
2.24
1.97
3.53
3.97
4.21
3.49
2.43
+0.59
2.29
2.10
4.82
2.51
5.03
3.59
3.21
2.65
2.83
6.27
2.62
2.50
2.60
3.89
4.45
3.07
Supporting information Droge et al. 2016
Table S3A. LogKOW values for primary and secondary amines
Amine type
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
CxHyN
1°
polar
1°
polar
1°
polar
1°
polar
1°
polar
1°
polar
1°
polar
1°
polar
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
CxHyN
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
2°
polar
#
2
3
4
5
50
51
28
75
6
9
10
13
15
17
18
19
24
29
31
32
33
34
42
49
54
58
59
61
77
Name
benzylamine
4-methylbenzylamine
4-butylbenzylamine
4-octylbenzylamine
2-phenylethylamine
amphetamine
3-phenylpropylamine
4-phenylbutylamine
4-t-butylcyclohexylamine
1-hexylamine
1-heptylamine
1-octylamine
1-decylamine
tert-octylamine
(±)-1-aminoindane
amantadine
1-naphthylmethylamine
1-naphthylamine
3,4-dimethylaniline
2,4,6-trimethylaniline
4-octylaniline
4-fluoroaniline
3-chloroaniline
4-chlorobenzylamine
3,4-dichlorobenzylamine
tryptamine
serotonin
dopamine
amlodipine
N-methylbenzylamine
N-ethylbenzylamine
N-butylbenzylamine
N-hexylbenzylamine
N-octylbenzylamine
3-methyl-N-methylbenzylamine
methamphetamine
N-methylphenethylamine
dibenzylamine
dicyclohexylamine
dihexylamine
N-ethylcyclohexylamine
N-methyloctylamine
N-methyldodecylamine
maprotiline
N-methylaniline
N-ethyl-M-toluidine
sertraline
fluoxetine
duloxetine
N-benzylaminoacet-aldehydediethylacetal
MDMA
bupropion
ketamine
ethyl 3-(benzylamino)-propanoate
N-ethanolbenzylamine
albuterol
alprenolol
nadolol
metoprolol
propranolol
prilocaine
atenolol
pindolol
timolol
1,3-diphenylguanidine
sotalol
acebutolol
S6
Experimental
1.09
1.46
1.41
1.76
1.83
2.40
2.06
2.57
2.90
2.44
2.25
1.84
1.15
1.88
1.55
0.21
-0.98
3.00
1.52
1.82
2.59
2.07
1.91
2.67
1.66
4.05
2.15
2.18
0.79
3.10
0.81
1.88
3.48
2.11
0.16
1.75
1.83
0.24
1.71
EPISuite
1.07
1.62
3.09
5.05
1.34
1.76
2.05
2.54
3.41
1.82
2.31
2.8
3.78
2.58
1.92
2.43
2.25
2.25
2.17
2.72
5.06
1.28
1.72
1.71
2.36
1.27
0.79
0.38
2.07
1.54
2.03
3.01
3.99
4.97
2.08
2.22
1.80
3.24
4.37
4.74
2.59
3.27
5.23
4.52
1.62
2.66
5.29
4.65
4.68
1.91
2.28
3.85
3.12
2.06
0.56
0.64
2.81
1.17
2.44
2.60
1.88
-0.03
1.48
1.75
2.89
0.37
1.19
ACD/Labs
1.09
1.55
3.14
5.27
1.46
1.81
1.83
2.36
3.12
1.99
2.52
3.06
4.12
2.32
1.61
2.22
2.32
2.17
1.90
2.30
5.12
1.15
1.81
1.68
2.15
1.38
0.21
0.12
4.16
1.52
2.05
3.11
4.18
5.24
1.98
1.94
1.60
3.42
3.69
4.88
2.16
3.29
5.41
4.50
1.60
2.59
4.81
4.09
3.73
3.25
1.81
3.47
2.18
2.41
1.12
0.01
2.88
1.29
1.79
3.10
1.74
0.10
1.97
0.68
2.36
0.32
1.95
Supporting information Droge et al. 2016
Table S3B. LogKOW values for tertiary amines
Amine type
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
CxHyN
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
3°
polar
#
1
7
8
12
14
16
23
25
27
30
35
36
37
38
39
40
41
43
44
52
53
55
56
57
62
63
64
65
66
67
68
69
70
71
11
60
73
74
76
78
79
80
81
82
83
84
85
Name
pyridine
quinoline
acridine
2-methylpyridine
3,4-lutidine
2,6-dimethylpyridine
2,4,6-collidine
N,N-dimethylbenzylamine
N,N-diethylbenzylamine
N,N-dimethyloctylamine
N,N,N-tributylamine
N,N,N-trihexylamine
N,N-dimethylcyclohexylam.
N,N-diethylaniline
imipramine
amitriptyline (HCl)
fenpropidin
deprenyl
diphenhydramine
escitalopram
spiroxamine
3-dimethylamino-propiophenone
cocaine
methylephedrine
2,2'-(benzylimino)-diethanol
tramadol
atropine
scopolamine
procaine
4-amino-2-methylquinoline
ropivacaine
bupivacaine
lidocaine
S-(-)-1-benzyl-3-acetamidopyrrolidine
propamocarb
benzimidazole
thiabendazole
(S)-(-)nicotine
clonidine
clotrimazole
sulpiride
morphine
naloxone
strychnine
harmine
harmaline
promazine
chlorpromazine
triflupromazine
doxepin
(±)-verapamil
trimethoprim
loperamide
ketanserin
nicardipine
lincomycin
diltiazem
amiodarone
ergocornine
nefopam
tiamulin
clarithromycin
erythromycin
tylosine
S7
Experimental
0.65
2.03
3.40
1.11
1.68
1.88
1.98
3.31
4.80
4.92
2.90
3.27
2.30
1.70
2.63
1.83
0.98
2.14
2.90
3.41
2.44
1.12
1.32
2.47
1.17
1.59
6.26
0.57
0.89
2.09
1.93
3.56
4.55
5.41
5.54
4.36
3.79
0.91
3.29
3.82
0.20
2.70
7.57
3.05
3.16
3.06
1.63
EPISuite
0.80
2.14
3.32
1.35
1.90
1.90
2.45
1.75
2.73
3.48
4.46
7.41
2.31
3.15
5.01
4.95
6.42
2.64
3.11
3.74
5.51
1.37
2.17
0.89
0.21
3.01
1.91
0.39
1.99
1.77
2.95
3.44
1.66
1.01
1.13
1.23
2.00
1.00
1.45
6.26
0.65
0.72
0.95
1.85
2.83
4.64
3.79
5.20
5.52
3.99
4.80
0.73
5.15
3.02
3.9
0.29
2.79
8.81
2.64
3.05
4.75
3.18
2.48
1.05
ACD/Labs
0.73
2.08
3.40
1.19
1.65
1.65
2.11
1.98
3.04
3.78
4.84
8.03
2.12
3.39
4.80
4.92
5.87
2.95
3.66
2.51
4.88
1.74
3.08
1.74
1.47
2.51
1.53
0.76
2.36
2.09
4.39
3.64
3.63
0.88
1.80
1.38
2.47
0.72
1.41
5.44
0.45
0.43
1.45
1.74
3.17
1.02
4.63
5.20
5.70
3.86
3.9
0.38
4.26
3.21
5.13
1.82
3.63
8.89
4.51
3.44
5.93
3.16
2.83
3.27
Supporting information Droge et al. 2016
Figure S1. Apparent sorption coefficients to IAM column material at various acetonitrile
mixtures with 10mM pH5.0 buffer (UV-HPLC or LC-MS/MS detection). Red bars on the yaxis represent 95% confidence intervals for the extrapolated logKIAM,aq value.
S8
Supporting information Droge et al. 2016
Figure S2. Surface charge density profiles of TZVP molecules
Top: DMPC-long.cosmo used in the COSMOmic example file
Bottom: DMPC-TZVP structure used in the Bittermann et al. 2014 study (1)
Difference between the two DMPC bilayer input systems for acids:
dinoseb
pentachlorophenol
2346-tetrachlorophenol
diclofenac
From Bittermann et al. 2014:
TUHH-DMPC (1 Gauss potential) - model M2
(logK L/kg) (no offset used, recommended to
be even 0.37 log units lower)
2.87
3.58
3.36
2.94
S9
COSMOmic
DMPC V15
(logK L/kg)
difference
(log units)
3.69
4.38
4.19
3.74
0.82
0.80
0.83
0.80
Supporting information Droge et al. 2016
logKDMPC-W = 1.717
Figure S3A. verapamil stretched TZVP conformation, from 2 different angles
logKDMPC-W =0.55
logKDMPC-W =0.51
logKDMPC-W =1.24
logKDMPC-W =0.72
logKDMPC-W =0.54
logKDMPC-W =0.41
Figure S3B. verapamil 6 optimized TZVP configurations via COSMOconf, each from 2
different angles
weighted logKDMPC-W = 0.63
S10