Advances in Structure–Activity Relationship Studies on Potassium Channel Modulators - Ion Channels and Their Inhibitors - page 259

Table 1 Compounds used in deriving 2D-QSAR and pharmacophore model of hERG K + channel
blockers [ 82 ]
Compounds
Amiodarone Domperidone Moxifloxacin Terfenadine

Amitryptiline Droperidol N-desmethyl-clozapine Thioridazine

Astemizole E-4031 Ofloxacin Vardenafil

Azimilide Flecainide Olanzapine Verapamil

Bepridil Gatifloxacin Ondansetron Ziprasidone

Chloroquine Granisetron Perhexiline Acrivastine

Chlorpheniramine Grepafloxacin Phenobarbital Amsacrine

Chlorpromazine Halofentrine Phenytoin Cocaine

Ciprofloxacin Haloperidol Pimozide Desmethylastemizole

Cisapride Imipramine Propafenone Desmethylcarboxyloratadine

Clozapine Lidocaine Pyrilamine Fentanyl

Clozapine-N-oxide Loratadine Queitiapine Fexofenadinec

Desipramine Lumefantrine Quinidine Ketoconazole

Diltiazem Mesoridazine Risperidone Lidoflazine

Diphenhydramine Mibefradil Sertindole Meperidine

Dofetilide Mizolastine Sparfloxacin Tadalafil

Dolasetron Mefloquine Spironolactone Cetrizine

relationship between the CoMSIA model and the hERG homology model built from
the crystal structure of the open bacterial MthK potassium channel [ 80 ]. The
CoMSIA and the hERG homology models led Pearlstein et al. to suggest that (a)
aromatic moieties optimally provide hydrophobicity and get involved in

p -stacking

with Phe 656 side chain, (b) basic nitrogen facilitates -cation interaction with Try

652, and (c) the ion pore diameter and depth act as constrains for the inhibitor
interaction [ 80 ].
Garg et al. [ 82 ] have modeled the hERG K + channel blocking activity of diverse
molecules (Table 1 ) selected from literature using Cerius2 and Catalyst software
[ 83 ]. The activity of these compounds (IC 50 ) against hERG K + channels was
expressed in mammalian cells lines. In Cerius2, using several electrotopological,
thermodynamic, ADMET, graph theoretical and physicochemical properties, the
2D-quantitative structure-toxicity relationship (2D-QSTR) was derived for the
hERG K + channel blocking activity of the compounds (Table 1 ).

p

pIC 50 ¼ 2 : 04746 þ 0 : 18227kappa3 1 : 61453 Atype O 57 þ 0 : 251155 S sNH2

1 : 97268 JX 0 : 969258 Atype O 59 þ 0 : 61608 ADMET PPB

0 : 063453 Atype H 46

r 2 Q 2

BS r 2

n ¼ ; ¼ : ; ¼ : ; ¼ : : ; ¼ : ;

56 0 837 0 776 0 838 0 001 LOF 0 5

r pred ¼ PRESS ¼ 16 : 06 ; 0 : 701 : (21)

The presence of topological descriptor, kappa3 (The Kier and Hall kappa shape
index of order 3), shows the importance of shape in exhibiting hERG K + channel