A similarity-based classifier using topomers to provide a ...

1

SUPPORTING INFORMATION

A similarity-based classifier using topomers to provide a

knowledge base for hERG channel inhibition

Britta Nisius and Andreas H. Göller

Bayer HealthCare AG, Global Drug Discovery, Lead Generation and Optimization, Aprather Weg 18a,

D-42096 Wuppertal, Germany

2

Table S1: Descriptors used to validate the use of neighbors with a Topomer Search distance up to 270

Descriptor Characterization

Mol_weight Molecular weight

AlogP The octanol-water partition coefficient

AlogP_MR Estimate of molecular refractivity

Num_Atoms Total number of atoms

Num_Hydrogens Number of hydrogens

Num_PositiveAtoms Number of positively charged atoms

Num_NegativeAtoms Number of negatively charged atoms

Num_RotatableBonds Number of rotatable bonds

Num_Rings Number of rings

Molecular_SurfaceArea Total surface area using a 2D approximation

Molecular_FractionalPolarSurfaceArea Ratio of polar surface area divided by the total surface area

Molecular_Volume 3D volume based on 3D coordinates

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Table S2: Dataset of 681 hERG patch-clamp measurements on mammalian cell lines (HEK, CHO,

COS) and corresponding references.

Name pIC50 Reference

(2R)-N-(4-tert-butylphenyl)-N'-cyano-4-(3-fluoropyridin-2-yl)-

2-methylpiperazine-1-carboximidamide 6.00 1

(4R)-4-(4-fluorophenyl)-8-[1-(4-fluorophenyl)cyclohexyl]-2,8-

diazaspiro[4.5]decan-1-one 5.89 1

(5aR,9R)-2,9-dimethyl-5,5a,6,7,8,9-

hexahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine 4.68 1

1,4-Dihydroindeno[1,2-c]pyrazol_50 5.28 2




1-{4-[({4-[(4-bromo-2-fluorophenyl)amino]-6-

methoxyquinazolin-7-yl}oxy)methyl]piperidin-1-yl}-2-

(dimethylamino)ethanone 5.82 1

1-{4-[2-({4-[(2,3-dimethyl-1H-indol-5-yl)oxy]-6-

methoxyquinazolin-7-yl}oxy)ethyl]piperazin-1-yl}propan-2-one 5.00 1

1-bis(4-fluorophenyl)methyl piperazine 5.80 3

2-Amino-N-pyrimidin-4-ylacetamide-1 6.02 4





2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)

(Racemate) 4.00

3

2-hydroxymethyl olanzapine 4.94 5



4,4-difluorobenzhydrol 4.00 3

4,4-difluorobenzophenone 4.14 3

4-Aminopyridine 2.40 6

4



5-chloro-N-(2,4-dimethoxybenzyl)-1-benzofuran-2-

carboxamide 4.78 1

5-chloro-N-[3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-

yl)propyl]-N-methyl-1-benzofuran-2-carboxamide 4.70 1

6-(4-chlorophenyl)-3-{4-[(3S)-3-hydroxypyrrolidin-1-yl]-3-

methoxyphenyl}thieno[3,2-d]pyrimidin-4(3H)-one 5.00 1

6-(4-chlorophenyl)-3-{4-[(3S)-3-hydroxypyrrolidin-1-yl]-3-

methoxyphenyl}thieno[3,2-d]pyrimidin-4(3H)-one 5.35 1

9-hydroxyrisperidone 5.89 7

9-hydroxyrisperidone 6.00 6

AF 3013 (NM-394) 3.00 3

Ajmaline 5.98 3

Alfuzosin 4.08 7

Alosetron 5.52 5

Alosetron 5.50 5

Alosetron 5.50 7

Alosetron 5.49 1

Alosetron 5.49 3

Alosetron 5.49 8

Aminomethyl-tetrahydronaphthalene-ketopiperazine 1 5.09 9

Aminomethyl-tetrahydronaphthalene-ketopiperazine 2a 5.48 9

Aminomethyl-tetrahydronaphthalene-ketopiperazine 2b 5.77 9

Aminomethyl-tetrahydronaphthalene-ketopiperazine 2c 5.48 9

Aminomethyl-tetrahydronaphthalene-ketopiperazine 2d 5.92 9

Aminomethyl-tetrahydronaphthalene-ketopiperazine 4a 5.70 9

Aminomethyl-tetrahydronaphthalene-ketopiperazine 4b 5.40 9

Aminomethyl-tetrahydronaphthalene-ketopiperazine 4e 4.96 9

Aminomethyl-tetrahydronaphthalene-ketopiperazine 4f 4.89 9

Aminomethyl-tetrahydronaphthalene-ketopiperazine 4g 4.62 9

5

Aminomethyl-tetrahydronaphthalene-ketopiperazine 4h 4.60 9

Aminomethyl-tetrahydronaphthalene-ketopiperazine 4i 4.60 9

Amitriptyline 5.00 5






Amsacrine 6.68 1

Amsacrine 6.68 8

Amsacrine 6.68 3

Amsacrine 6.67 5

Aripiprazole 6.20 1

Articaine 3.65 12

Astemizole 8.00 10

Astemizole 9.05 7

Astemizole 9.04 11

Astemizole 9.04 5

Astemizole 8.89 1

Astemizole 8.89 1

Astemizole 7.94 8

Astemizole 7.89 1

Astemizole 7.68 1

Astemizole 9.05 3

Atenolol (Racemate) 3.00 3

AVE-0118 5.00 1

Azimilide 6.25 7

Azimilide 6.25 6

Azimilide 6.25 11

6

Azimilide 6.22 5

Azimilide 6.21 6

Azimilide 5.85 10

BAPTA-AM 5.88 13

BCTC 6.00 1

Benperidol 8.47 14

Benzoylecgonine 3.00 1

Benzoylecgonine 3.41 1

Bepridil 6.26 10

Bepridil 6.62 11

Bepridil 6.26 5

Bepridil 6.26 6

Bepridil 6.26 3

Bepridil 7.64 8

Bepridil 7.59 7

Berberine 5.51 3

Bicifadine 4.34 1

Bisindolylmaleimide 6.00 3

BMCL_03_13_1829-1835_1 7.06 3

BMCL_03_13_1829-1835_10 8.21 3

BMCL_03_13_1829-1835_12 4.00 3

BMCL_03_13_1829-1835_14 6.69 3

BMCL_03_13_1829-1835_15 7.96 3

BMCL_03_13_1829-1835_16 4.59 3

BMCL_03_13_1829-1835_17 5.83 3

BMCL_03_13_1829-1835_18 5.34 3

BMCL_03_13_1829-1835_19 5.71 3

BMCL_03_13_1829-1835_2 8.00 3

BMCL_03_13_1829-1835_20 4.80 3

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BMCL_03_13_1829-1835_21 5.66 3

BMCL_03_13_1829-1835_22 5.46 3

BMCL_03_13_1829-1835_23 4.00 3

BMCL_03_13_1829-1835_3 8.15 3

BMCL_03_13_1829-1835_4 6.24 3

BMCL_03_13_1829-1835_5 4.12 3

BMCL_03_13_1829-1835_7 6.88 3

BMCL_03_13_1829-1835_8 7.44 3

BMCL_03_13_1829-1835_9 4.00 3

BMCL_2006_1207_19 5.46 15

BMCL131829-02 8.00 7

BMCL131829-05 5.13 7

BMCL131829-11 6.34 7

BMCL131829-16 4.59 7

BMCL131829-17 5.83 7

BRL-32872 7.70 3

BRL-32872 7.70 3

Brompheniramine 5.76 16

Brompheniramine maleate 6.05 16

Buprenorphine 5.10 6

Canrenoic Acid 3.98 7

Carbamazepine 2.52 17

Carvedilol 6.29 1

Carvedilol 6.29 3

Chlorobutanol 2.36 3

Chloroquine 5.60 1

Chloroquine 5.60 6

Chloroquine 5.60 5

Chloroquine 5.60 3

8

Chlorpheniramine 4.89 1

Chlorpheniramine 4.89 3

Chlorpromazine 5.83 5









Chromanolol 293B 4.26 18

Chromanolol 293B 5.18 15

Cibenzoline 5.43 3

Cimetidine 2.00 1

Ciprofloxacin 3.02 5






Citalopram 5.40 7

Citalopram 5.40 8

Citalopram 5.40 3

CJ-033466 5.59 19

Clarithromycin 4.48 1

Clarithromycin 4.04 1

Clebopride 6.21 20

Clemastine 7.92 21

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Clenbuterol 4.10 5

Clomifene 6.74 5

Clomifene 6.74 8

Clozapine 6.59 8

Clozapine 6.50 7

Clozapine 6.49 1

Clozapine 6.49 3

Clozapine 6.49 6

Clozapine 5.60 1

Clozapine 5.35 5

Cocaethylene 5.92 1

Cocaine 5.36 1

Codeine 3.00 3

Codeine 3.52 5

Cyamemazine 6.33 3

Desbutyl-lumefantrine 5.26 6

Desipramine 6.00 6

Desipramine 5.86 5

Desipramine 5.86 8

Desipramine 5.86 7

Desipramine 5.86 3

Desmethylolanzapine 4.85 3

Desmethylastemizole 9.00 10





Diltiazem 4.77 5

Diltiazem 4.76 7

10

Diltiazem 4.76 11

Diltiazem 4.76 10

Diltiazem 4.76 8

Diphenhydramine 5.59 8

Disopyramide 5.14 7

Disopyramide 5.14 3

Dofetilide 8.00 1

Dofetilide 8.00 3

Dofetilide 8.00 7

Dofetilide 7.96 1

Dofetilide 7.96 3

Dofetilide 7.32 6

Dofetilide 8.02 3

Dofetilide 8.00 10

Dofetilide 7.92 1

Dofetilide 7.92 3

Dofetilide 7.92 6

Dofetilide 7.92 5

Dofetilide 7.91 11

Dofetilide 7.91 8

Dofetilide 7.82 1

Dofetilide 7.82 1

Dofetilide 7.82 3

Dolasetron 5.23 1

Dolasetron 5.07 1

Domperidone 6.79 1

Domperidone 6.79 3

Domperidone 6.79 7

Domperidone 6.79 8

11

Domperidone 6.79 5

Domperidone 6.79 11

Doxazosin 6.23 7

Doxazosin 6.23 5

Doxazosin 6.23 8

Doxazosin 6.23 3

Doxepin 5.19 22

Dronedarone 7.23 5

Droperidol 7.49 7

Droperidol 7.49 8

Droperidol 7.49 1

Droperidol 7.49 7

Droperidol 7.49 5

DW-224a 3.66 20

E-4031 8.06 3

E-4031 6.87 3

E-4031 6.87 6

E-4031 7.55 6

E-4031 8.11 3

E-4031 8.11 6

E-4031 8.11 11

E-4031 7.92 8

E-4031 7.74 6

E-4031 7.74 3

E-4031 7.74 7

E-4031 7.74 5

E-4031 7.58 6

Ecgoninemethylester 3.00 1

Ecgoninemethylester 3.38 1

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EDDP(Edifenphos) 4.30 5

EGCG 5.22 23

Eliprodil 7.70 1

EMD-60263 5.18 15

ER-118585 7.40 3

Erythromycin 4.26 1

Erythromycin 4.23 1

Erythromycin 4.14 1

Erythromycin 4.02 1

Erythromycin 3.82 1

Erythromycin 3.80 1

Erythromycin 3.41 1

Erythromycylamine 3.56 7



Estradiol 4.00 3

Famotidine 5.00 1

Fentanyl 5.74 3

Fentanyl 5.75 5

Fexofenadine 4.64 7

Fexofenadine 4.64 3

Fexofenadine 4.67 5

Fexofenadine 4.67 10

Fexofenadine 4.67 8

Flecainide 5.41 5

Flecainide 5.41 8

Flecainide 5.41 7

Flecainide 5.41 1

Flecainide 5.41 6

13

Flecainide 5.41 3

Fluoxetine 5.82 7

Fluoxetine 6.34 8

Fluoxetine 5.82 3

Fluvoxamine 5.42 3

Fluvoxamine 5.50 3

Gatifloxacin 3.89 11

Gatifloxacin 3.89 10

Gatifloxacin 3.89 1

Gatifloxacin 3.89 7

Gatifloxacin 3.89 3

Gatifloxacin 3.89 5

Gatifloxacin 3.89 8

GF109203X 6.00 5

Grepafloxacin 4.36 5






Halofantrine 6.71 5

Halofantrine 6.71 6

Halofantrine 6.70 11

Halofantrine 6.70 10

Halofantrine 7.67 7

Halofantrine 7.67 6

Halofantrine 7.51 8

Halofantrine 7.40 6

Haloperidol 7.73 1

14

Haloperidol 7.50 7

Haloperidol 7.49 1

Haloperidol 7.49 3

Haloperidol 7.72 8

Haloperidol 7.57 1

Haloperidol 7.57 3

Haloperidol 7.57 5

Haloperidol 7.57 6

Haloperidol 7.55 11

Haloperidol 7.52 10

Haloperidol 7.20 1

Haloperidol 7.20 3

Haloperidol 7.05 1

Haloperidol 6.76 1

Haloperidol 6.76 1

HY-2901 5.00 1

ICI 118551 5.04 3

Ifenprodil 7.00 1

Imipramine 5.47 11

Imipramine 5.47 5

Imipramine 5.47 10

Imipramine 5.47 8

Imipramine 5.47 7

Imipramine 5.47 3

Indometacin 3.52 1

Irbesartan 3.71 3

Irbesartan 3.71 7

Isradipine 5.00 5

Isradipine 4.00 3

15

Josamycin 3.99 6

Josamycin 3.99 1

Ketanserin 6.97 8

Ketoconazole 5.72 10

Ketoconazole 5.77 1

Ketoconazole 5.72 5

Ketoconazole 5.72 1

Ketoconazole 5.72 7

Ketoconazole 5.72 8

Ketoconazole 5.70 6

Ketoconazole 5.63 1

Ketoconazole 5.36 1

Ketoconazole 5.33 1

L-alpha-Acetylmethadol 5.61 6

Lamotrigine 3.64 5

Levofloxacin 3.04 5

Levofloxacin 3.04 10

Levofloxacin 3.04 7

Levofloxacin 3.04 1

Levofloxacin 2.85 8

Levofloxacin 3.37 1

Lidoflazine 7.80 3

Lidoflazine 7.43 1

Lidoflazine 7.80 8

Lidoflazine 7.79 5

Lidoflazine 7.78 6

Lignocaine 3.58 6

Lignocaine 3.58 7

Lignocaine 3.58 3

16

Lomefloxacin 2.62 24

Lopinavir 5.07 1

Loratadine 6.77 10

Loratadine 6.76 7

Loratadine 6.76 6

Loratadine 6.76 11

Loratadine 6.76 5

Loratadine 5.64 8

Loratadine 5.52 1

Loratadine 5.40 1

Loratadine 5.40 3

Loratadine 6.76 3

Lovastatine 5.15 1

Lumefantrine 5.09 1

Lumefantrine 5.10 5

Lumefantrine 5.09 8

Lumefantrine 5.09 6

LY-97241 8.66 1

LY-97241 8.66 1

M-43068 3.52 1

Maraviroc 5.00 1

MDL-74156 4.92 1

MDL-74156 5.07 1

Mefloquine 5.25 7

Mefloquine 5.25 5

Mefloquine 5.59 8

Mefloquine 5.58 6

Meperidine 4.12 3

Meperidine 4.13 5

17

Mepivacaine 3.81 3

Mesoridazine 6.49 1

Mesoridazine 6.36 15

Mesoridazine 6.49 3

Mesoridazine 6.26 3

Methadone 5.01 5

Methadone 5.00 6

Methadone 5.01 3

Methadone 4.70 3

Methylecgonidine 3.76 6

Metoclopramide 5.27 5

Metoprolol 3.84 3

Mexiletine 5.00 5

Mibefradil 6.00 6

Mibefradil 5.84 1

Mibefradil 5.84 11

Mibefradil 5.84 10

Mibefradil 5.96 1

Miconazole 5.68 1

Miconazole 5.68 3

Miconazole 5.68 5

Misolastine 6.36 8

Mizolastine 6.46 7

Mizolastine 6.46 6

Mizolastine 6.45 11

Mizolastine 6.36 10

Mizolastine 6.46 7

Mizolastine 6.46 5

MK-499 7.68 15

18

Morphine 3.00 3

Morphine 3.00 5

Mosapride 5.32 19

Moxifloxacin 3.93 11

Moxifloxacin 3.89 7

Moxifloxacin 4.13 6

N-{(1S)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl}-N-

methyl-2-(4-{[(methylsulfonyl)amino]methyl}phenyl)acetamide 5.00 1

Naringenin 4.44 1

N-Demethylclozapine 5.35 1

N-Demethylerythromycin 3.83 6

N-Demethylolanzapine 4.85 6

N-Desbutylhalofantrine 7.14 6





N-Desmethylclozapine 5.35 15

Nelfinavir 4.94 1

Nicotine 3.61 1

Nifedipine 4.30 5

Nifedipine 4.30 10

Nifedipine 4.00 3

NIP-142 4.36 1

Nitrendipine 5.00 5

Nitrendipine 5.00 1

Nitrendipine 5.00 10

Noracetylmethadol 4.92 25

Norastemizole 7.56 5

19




Norclozapine 5.35 7

Norclozapine 5.40 6

Norfluoxetine 5.64 1

Norfluoxetine 5.60 1

Olanzapine 5.22 3

Olanzapine 5.22 1

Olanzapine 6.74 10

Olanzapine 6.74 8

Olanzapine 6.64 6

Olanzapine 6.64 7

Olanzapine 6.64 1

Olanzapine 6.63 5

Ondansetron 6.09 10

Ondansetron 6.09 7

Ondansetron 6.09 6

Ondansetron 6.09 5

Ondansetron 6.09 8

Ondansetron 6.09 3

Orphenadrine 6.07 26

Oxatomide 6.45 1

Paliperidone 5.89 1

Perhexiline 5.11 5

Perhexiline 5.11 10

Perhexiline 5.11 8

Perhexiline 5.11 7

Perhexiline 5.11 3

20

Perhexiline 5.11 11

Perphenazine 6.00 1

Perphenazine 6.00 3

Phenobarbital 2.52 3




Phenytoin 3.62 3

Phenytoin 3.62 5

Phenytoin 3.62 8

Phenytoin 3.62 6

Pilsicainide 4.69 3

Pilsicainide 4.70 5

Pilsicainide 4.69 8

Pimozide 7.75 7

Pimozide 7.74 1

Pimozide 7.74 1

Pimozide 7.74 3

Pimozide 7.74 1

Pimozide 9.00 8

Pimozide 8.00 1

Pimozide 7.92 1

Pimozide 7.74 11

Pimozide 7.30 10

Pimozide 7.26 1

Pimozide 7.26 3

Pimozide 7.26 6

Pimozide 7.26 5

Prazosin 5.81 5

21

Prazosin 5.80 7

Prazosin 5.80 8

Prazosin 5.80 3

Prenylamine 6.23 3

Procainamide 3.86 8

Procainamide 3.86 6

Procainamide 3.86 3

Propafenone 6.36 5

Propafenone 6.36 7

Propafenone 6.36 1

Propafenone 6.36 6

Propafenone 5.70 1

Propafenone 6.36 3

Propafenone 5.70 3

Protriptyline 5.93 27

Prucalopride 5.22 6

Prucalopride 5.39 28

Prulifloxacin 3.46 1

Pyrilamine 5.22 3

Quetiapine 5.24 5

Quetiapine 5.24 7

Quetiapine 5.24 3

Quinidine 6.39 6

Quinidine 6.39 1

Quinidine 6.12 1

Renzapride 5.70 6

Risperidone 6.82 10

Risperidone 6.78 1

Risperidone 6.78 3

22

Risperidone 6.58 1

Risperidone 7.00 1

Risperidone 6.83 7

Risperidone 6.83 1

Risperidone 6.83 3

Risperidone 6.83 6

Risperidone 6.83 5

Risperidone 6.79 8

Risperidone 6.42 1

Risperidone 6.40 1

Ritonavir 5.09 1

Roxithromycin 4.44 1

Saquinavir 4.82 1

Saquinavir 4.82 1

Saxitoxin 6.52 6

Saxitoxin 5.25 6

Sertindole 8.57 1

Sertindole 8.52 7

Sertindole 8.52 1

Sertindole 7.19 1

Sertindole 8.57 3

Sertindole 8.52 3

Sertindole 8.30 1

Sertindole 8.00 10

Sertindole 7.90 8

Sertindole 7.85 11

Sertindole 7.83 1

Sertindole 7.83 5

Sertindole 7.82 6

23

Sertindole 6.68 1

Sertindole 7.85 3

Sertindole 7.83 3

Sertindole 6.68 3

Sildenafil 5.52 6

Sildenafil 5.48 1

Sildenafil 5.48 3

Sildenafil 5.48 7

Sildenafil 4.48 1

Sildenafil 4.48 3

Sildenafil 4.02 1

Sildenafil 4.00 11

Sildenafil 4.00 8

Sildenafil 4.00 6

Sildenafil 5.48 5

Sophocarpine 3.70 29

Sotalol 3.57 15

Sparfloxacin 4.74 1

Sparfloxacin 4.60 1

Spironolactone 4.64 1

Spironolactone 4.64 7

sulfamethoxazole 2.00 5

Tadalafil 4.00 1

Tamsulosin 3.98 7

Telithromycin 4.34 1



Terazosin 4.76 5

Terazosin 4.75 7

24

Terazosin 4.75 8

Terazosin 4.75 3

Terfenadine 7.25 7

Terfenadine 7.25 1

Terfenadine 7.25 3

Terfenadine 8.08 8

Terfenadine 8.06 1

Terfenadine 8.03 1

Terfenadine 7.96 1

Terfenadine 7.80 1

Terfenadine 7.80 1

Terfenadine 7.42 1

Terfenadine 7.28 1

Terfenadine 7.25 1

Terfenadine 7.25 1

Terfenadine 6.89 11

Terfenadine 6.70 10

Terfenadine 6.69 7

Terfenadine 6.67 1

Terfenadine 6.67 6

Terfenadine 6.67 5

Terfenadine 7.25 3

Terfenadine 6.69 3

Terfenadine 6.67 3

Thioridazine 6.72 1

Thioridazine 6.65 1

Thioridazine 5.97 1

Thioridazine 6.72 3

Thioridazine 6.65 3

25

Thioridazine 5.97 3

Thioridazine 7.48 6

Thioridazine 7.48 5

Thioridazine 7.48 7

Thioridazine 7.48 1

Thioridazine 7.45 11

Thioridazine 7.02 8

Thioridazine 6.41 1

Thioridazine 7.48 3

Thioridazine 6.41 3

Trazodone 6.16 3

Trazodone 5.54 3

Trazodone 6.16 30

Trazodone 5.54 31

Trazodone 5.54 5

Trazodone 5.54 8

Trifluoperazine 5.85 3

Trifluoperazine 5.04 5

Trimetoprim 3.62 5

Trimetoprim 3.62 10

Ulifloxacin 3.46 1

Vardenafil 4.92 1

Vardenafil 4.90 5

Vardenafil 4.89 3

Vardenafil 4.89 8

Verapamil 6.84 1

Verapamil 6.08 1

Verapamil 7.03 7

Verapamil 7.03 1

26

Verapamil 6.87 8

Verapamil 6.85 10

Verapamil 6.84 1

Verapamil 6.84 11

Verapamil 6.84 5

Verapamil 6.67 6

Verapamil 6.39 1

Verapamil 6.27 1

Verapamil 6.15 1

Verapamil 6.67 3

Verapamil 6.84 3

Vesnarinone 6.00 6

Vesnarinone 5.98 7

Vesnarinone 5.97 1

Vesnarinone 5.97 3

Vesnarinone 5.96 8

Vesnarinone 5.96 5

Vinpocetine 6.89 32

Ziprasidone 6.77 3

Ziprasidone 6.90 6

Ziprasidone 6.90 7

Ziprasidone 6.90 5

Ziprasidone 6.90 8

Ziprasidone 6.90 3

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