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Home , Cromakalim, Gambierol

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A Anxiety disorders, 55 A–803467, 98 APD. See duration Absorption, distribution, metabolism, Arrhythmias, 45, 46 elimination and toxicity Aryl sulfonamido indanes, 126–128, 130 (ADMET), 193 ATP-sensitive potassium channels (KATP Absorption, distribution, metabolism, channels), 61 excretion, and toxicity Atrial effective refractory period (AERP), 122, (ADMET), 68 124–126, 128, 129, 132, 138 Acetylcholine binding protein (AChBP), Autoimmune diseases, 254 61, 62, 64 AZD7009, 101 Acetylcholine receptor (AChR), 57, 64 , 139 Action potential duration (APD), 120, 122, 123, 128, 132 B Action potentials, 243, 256, 259 Basis set, 69–70 ADME/T, 299, 304 b-Barrel membrane proteins AERP. See Atrial effective refractory period genome-wide annotation, 13 Agitoxin (AgTX), 60 machine-learning techniques Agonists, 59–61, 64 residue pair preference, 11 Alinidine, 40–42 TMBs, 10 ALS. See Amyotrophic lateral sclerosis pipeline, genomic sequences, 14 Alzheimer, 55, 61 statistical method, 9–10 AMBER, 61, 65 Bending hinge, 64 2-Amino–2-imidazolidinone, 123, 125 Benzanilide, 256–257 Ammi visnaga, 254 Benzimidazolone, 256–257 b-Amyloid peptide (Ab), 62–63, 65 , 140 Amyotrophic lateral sclerosis (ALS), 90, 94, Benzodiazepines, 245 101 Benzopyrane, 127–128 Anionic channel blockers Benzopyrans, 61, 246–251, 261 mechanism of action of, 329–330 Benzothiadiazine 1,1-dioxide, 252–254 Antagonists, 59, 60 Benzothiadiazines, 253 Antiarrhythmic, 65–66, 68, 99, 101 Benzothiazepine, 70 Antiarrhythmic agents Benzothiazine derivatives, 251–252 class I, 245 Benzotriazole, 256–257 class II, 245 Bestrophins, 321, 322, 330, 331 class III, 245 Big potassium channels (BK channels), Antidepressant, 65–67 256, 257 Antiepileptic, 46 , 56, 58, 59, 64, 69, 140

S.P. Gupta (ed.), Ion Channels and Their Inhibitors, 341 DOI 10.1007/978-3-642-19922-6, # Springer-Verlag Berlin Heidelberg 2011 342 Index

C agents acting on other Cl–channels Ca2+-activated chloride channels, 316–317, disulfonic stilbene, 327 321, 327, 330, 331 flufenamic acid, 327 Ca2+/calmudulin-dependent protein kinase II, indanylooxyacetic acid, 327, 328 317 niflumic acid, 327 Calcium antagonist, 271, 273–275, 278 NPPB, 327 , 69, 70 TS-TM-calix(4)arene, 327 Calcium blockers, 267–282 agents acting with in cAMP. See Cyclic adenosine monophosphate muscle cells cAMP-dependent kinase, 316 anthracene–9-carboxylate, 324 Cancer, 55 DIDS, 324 breast, 91, 103 ethacrynic acid, 324, 325 prostatic, 91 , 324, 325 , 93–98, 102 SITS, 324 Cardiac arrhythmias, 68 stilbene disulfonate, 324, 325 Cardiovascular, 55 Chloride ion channels Cardiovascular diseases, 86, 89–90, 99–101 activation of, 311, 317, 323 Carvedilol, 59 blockers of, 311, 322–330 Catalyst software, 259 classification of, 311–321 Cerius2, 259 gating mechanisms of, 311, 330 cGMP-dependent kinase, 316 human diseases related to, 322 Channelopathies, 85–89 mutations in, 311, 322, 331 Channels, 79–103 Chloroquine, 66 closed, 81, 83, 93 Cholecystokinin-B receptor antagonists, 245 open, 81–84 Chromane, 246 Channels and pores, 25 Chromanols, 249–251 CHARMM, 61 ChTX. See Charybdotoxin (ChTX), 60 Cilobradine, 41–43 Chemoinformatics, 298–303 CLC chloride channels Chloride intracellular channels (CLICs) Cl–permeation of, 314–315 biophysical properties of, 320–321 dimeric structure of, 312, 314 CLIC5B, 319–320 dimorphic existence of, 312 dimorphic form of, 320 double-barreled structure of, 312 family of, 320 family of, 312, 315–316 functions of, 321 gating of, 314–315 integral membrane protein form of, 321 pore of, 314–315 soluble globular protein form of, specification of, 315–316 320, 321 topological features of, 312–314 structure of, 320 CLICs. See Chloride intracellular channels Chloride ion channel blockers Clonidine, 40–42 agents acting at neuronal chloride channels Cluster analysis, 61 bicuculline, 323 Cognitive deficits, 88, 91 cyanotriphenylborate, 324 Combinatorial protocol in multiple linear pentylenetetrazole, 324 regression (CP-MLR), 248, 253 picrotin, 323 Comparative molecular field analysis picrotoxinum, 323 (CoMFA), 66–68 agents acting on epithelial chloride Comprehensive Descriptors for Structural and channels Statistical Analysis (CODESSA), , 325, 326 244, 257 diphenylamine carboxylate, 325, 326 Computational chemistry, 58, 70 , 325, 326 Conductance, 57, 62–63, 69 gluconate, 325, 326 Continuum, 70 organic anions, 325 Coordination numbers, 70–71 Index 343

CP-MLR. See Combinatorial protocol in Epithelial cells multiple linear regression cystic fibrosis airway, 317, 322, 330 Cromakalim, 246–249 normal, 317 Cyclic adenosine monophosphate (cAMP), Epithelial Na+ conductance (ENaC), 316 35, 37–40 Epithelium reticulum (ER), 321, 331 Cystic fibrosis transmembrane conductance ERP. See Effective refractory period regulator (CFTR) Extracellular ligand-activated channels, 243 mutations in, 316 nucleotide binding folds (NBFs) of, 316, 317 F regulatory R domain of, 317 F15845, 101 structure of, 316, 317 f-channel, 39, 40, 43, 45 FLAP, 61 Functional discrimination, membrane proteins D channels and pores, 25 3D-approaches, 244 characteristic features, amino acid residues, Deformation, 64 21–23 Depolarization, 82, 84, 88–90, 92, 93 databases, 18–21 Descriptors, 61, 66–68 ion channel proteins, 26 DHPs. See Dihydropyridines transporters based on classes and families, Diabetes, 61 23–25 Dihydropyrazolopyrimidine, 136 transporters from globular proteins, 21 Dihydropyridines (DHPs), 268–279, 281, 282 Dipole moments, 70 Diseases, 55, 57, 61 G 1,8-Disubstituted naphthalene, 130 GA. See Genetic algorithm 2,4-Disubstituted–1,2,3-triazoles, 124 GABA. See Gamma-aminobutyric acid 3D molecule representation of structures based GABA receptors on electron diffraction (3D MoRSE), blockers of, 323 253, 254 disorders associated with, 319 Docking, 58–64, 71 expression of, 319 1D-QSAR model, 206–207 functions of, 319 2D-QSAR model, 201–206, 244, 259 molecular structures of, 318–319 3D-QSAR model, 198–201 Gambierol toxin, 63 DRAGON, 244, 253 Gamma-aminobutyric acid (GABA), 58–60 “Drain plug” model, 196 Gating, 56, 57, 59–60, 64 , 122 Gating mechanism, 59, 60, 62 Drug-induced QT prolongation Genetic algorithm (GA), 58 cardiac , 161 Genetic function approximation (GFA), 244 class-III antiarrhythmic drugs, 161–162 Genetic partial least squares (G/PLS), 244 drug development, 160 Geometry optimizations, 69–70 proarrhythmic drugs, 162–163 Ginkgolide, 59 ventricular action structure, 161 Glycine receptor (GlyR), 59, 64 Drug trapping, 218–220 blockers of, 323 G/PLS. See Genetic partial least squares GRIND, 61 E Gromacs, 61 EasyDock, 60 Effective refractory period (ERP), 120 Electrostatic potential, 60 H Endoplasmic reticulum (ER), 156 Hanatoxin (HaTx1), 58–60 Ensemble, 67–68 hASIC. See The human acid-sensing ion Epilepsy, 55, 86–87, 91–94, 96, 103 channel 344 Index

HCN1. See Hyperpolarization-activated cyclic , 173 nucleotide-gated 1 , 173–174 HD. See Huntington disease and , 174 Hepatitis C, 62 chemical structure, year of approval/ hERG. See The human ether-a-go-go related withdrawal and medical indication, gene 165–171 hERG channel inhibition and E–4031, 174 bad ADMET profile, 193 fluconazol and fluoxetine, 174–175 ligand-based approaches grepafloxacin and , 175 classification models, 207–216 levacetylmethadol, 175 1D-QSAR, 206–207 macrolides (), 175–176 2D-QSAR, 201–206 mesoridazine and , 176 3D-QSAR, 198–201 nelfinavir, 176 matched molecular pairs, 216–217 , 176–177 pharmacophore models, 195–198 , 177 LQT syndrome, 193–194 risperidone, 177–178 structure and , 178 C terminus domain role, 195 , 178 regions, 194 Kv 11.1 mutations, 153 structure-based approaches preclinical guidelines, 179–180 amino acids involvement, 220–222 properties, 153 binding affinity model, 225–226 protein trafficking binding interactions, 225 chemical chaperones, 157–158 docking results, 229–232 ER, 156 docking studies, 227–228 glycosylation, 156 drug trapping, 218–220 pharmacological restoration, 158 Gly648 role, 223 4-phenylbutyrate, 157 homology models, 217–218 protein synthesis, 157 hydrogen bonds with Thr623, Ser624 temperature-dependent induction, 157 and Val625, 222–223 QTc, 159–160 orthogonal binding site, 229 strategies, QT prolongation, 182–183 para-substituents influence on phenyl structure ring, 224–225 N-terminal region, 155 subunits involvement, 223–224 S5–P–S6 sequences, 151–152 hERG potassium (K+) channels, 258–260 S1–S4 segments, 152 activators VSDs, 155 MTX, 173 Tdp, 158–159 NS1643, 173 as therapeutic target, 163–164 NS3623, 173 voltage-gated, 151 PD–118057, 172 Hidden Markov model (HMM), 6–7 RPR260243, 172 Homology modeling, 62–63 assay to predict QT prolongation The human acid-sensing ion channel electrophysiological studies, (hASIC), 59 mammalian cell lines, 182 Human diseases related to Cl–channels in silico methods, 180–181 alcoholism, 322 in vitro assay, 181–182 Bartter syndrome, 322 in vivo method, 182 Best’s disease, 322 cardiovascular safety, 178–179 cystic fibrosis, 322 classification, 151, 154 glioma in brain, 322 clinical guidelines, 180 hyperekplexia, 322 drug-induced QT prolongation, 160–163 insomnia, 322 functions and dysfunctions, 155–156 myotonia congenita Becker, 322 inhibitors myotonia congenita Thomsen, 322 Index 345

The human ether-a-go-go related gene Lambert-Eaton, 55 (hERG), 58, 59, 62, 63, 65–68 , 94, 96, 98, 101, 102 Huntington disease (HD), 90 Leak channels, 243 Hydrophobic, 60, 61, 64, 68 Levcromakalim, 246 a-Hydroxy-a-phenylamides, 103 Ligand-based approaches Hyperpolarization-activated cyclic classification models nucleotide-gated 1 (HCN1), 35–37, Bayes classification technique, 210 39, 42, 44, 46 Binary QSAR, 211 HypoGen, 260 chemical scaffolds, 208 counter-propagation neural network (CPG-NN), 211–213 I decision tree approach, 213–216 , 60 GRIND descriptors, 210–211 , 57, 64 linear solvation energy relationship Inactivation (LSER) descriptors, 209 fast, 82–84, 88, 89 1 mM and 40 mM thresholds, 207 slow, 84, 89, 94, 97 molecular fragments analysis, Incremental construction algorithm, 58 209–210 Insulin, 243, 247–248, 252 prediction method, 208 Intracellular ligand-gated ion channels, 243 Random Forest (RF), 212 Inwardly rectifying potassium (Kir), 59, 67 SVM, 209, 210, 213 Kir2.1, 58, 59, 65 1D-QSAR, 206–207 Kir6.2, 59 2D-QSAR, 201–206 Ion channels 3D-QSAR, 198–201 atypical, 321 matched molecular pairs, 216–217 blockers, 53–71 pharmacophore models ligand-gated, 311, 330 “build up” method, 196 Na+,K+,Ca2+,Cl–, 310, 311 charged nitrogen group, 195 voltage-gated, 311 “drain plug” model, 196 Ion conduction, 70 hERG blockers, 197, 198 Ionotropic receptors, 311, 317, 330 toxicophore, 197 Isoforms, 85, 86, 98, 99, 103 Ligand-gated Cl–channels (LGICs) Isoquinoline, 129–130 g-aminobutyric acid (GABA)-activated, Ivabradine, 41, 43–45 311 pore structure of, 318 Linear constraint solver (LINCS), 65 K Long QT (LQT) syndrome, 193–194 KATP channels. See ATP-sensitive potassium Loop, 81–84 channels KC12292, 99 KCOs. See openers M KcsA, 57, 69–71 Mallotoxin (MTX), 173 Khellinone, 254 Matched molecular pairs, 216–217 Khellinone derivatives, 254–256 (MTX), 63 Kinetics, 64 MD. See Molecular dynamics Kir. See Inwardly rectifying potassium Membrane, 81–84, 87, 89–94, 98, 103 Kv. See Voltage-gated potassium channel Membrane proteins databases list, 4 L PDB, 3–4 L–768,673, 245 description, 2 , 94, 97 drug–target interactions, 26–27 346 Index

Membrane proteins (cont.) Outward rectifying chloride channels (ORCC), functional discrimination 316 channels and pores, 25 Oxacarbazepine, 97 characteristic features, amino acid residues, 21–23 databases, 18–21 P ion channel proteins, 26 Pacemaker heart, 39, 40 transporters, different classes and Pain, 86–88, 91, 94–98, 101, 103 families, 23–25 inflammatory, 87, 94–95 transporters from globular proteins, 21 neuropathic, 87, 94–98 structural discrimination Pancreas, 243, 247–248, 252, 253 b-barrel membrane proteins, 9–13 Parkinson, 55 spanning b-strand segments, 13–17 Parkinson disease (PD), 90, 101 TMH proteins, 4–8 Partial least square (PLS), 244, 247, 251 TMS proteins, 8–9 Patch clamp, 57, 59 TMH and TMS proteins, 2 PcTx1. See Psalmotoxin 1 transporters, 3 PD. See Parkinson disease Membrane spanning b-strand segments Pentameric proteins, 317, 318 machine-learning techniques, 16–17 Pharmacophore, 67 statistical methods, 14–15 , 92–96, 98, 99, 103 , 67 Plasma membrane, 311, 312, 316, 317, 330, Migraine, 86, 88, 91, 96, 98 331 Molecular dynamics (MD), 57–65, 70, 71 Plateau, 128, 132 Molecular mechanics–Poisson Boltzmann/ Pore-forming region (P-region), 119 surface area (MM-PBSA), 60, 61, 65 “Positive-inside rule” concept, 6 Molecular orbital partial atomic charge Potassium channel, 117–142 (MOPAC), 244 Potassium channel openers (KCOs), 61 Moricizine, 99 Prialt, 290, 292, 294, 295 MS. See Principle components regression (PCR), 244 MTX. See Mallotoxin; Maurotoxin Protein Data Bank (PDB), 3–4 Multiple sclerosis (MS), 90, 101, 254 Psalmotoxin 1 (PcTx1), 58, 59 Muscimol, 60 Myorelaxant, 246, 249, 252, 253 Myotonic syndromes, 86, 88–89, 98–99 Q QM/MM. See Quantum mechanics/molecular mechanics N QSAR. See Quantitative structure activity Nav1.4, 67 relationships Nervous system, 34, 35, 39, 46 QT interval correction (QTc), 159–160 N-methyl-D-aspartate (NMDA) receptor, 60 QT-prolonging, 65–67 N,N-diisopropyl amide, 135 Quantitative structure activity relationships Notch, 128 (QSAR), 65–68, 71, 273, 274, 276–278, 281, 282 Quantum mechanics/molecular mechanics O (QM/MM), 70–71 Other Cl–transporting systems , 120, 140 apolar cells, 328, 329 Quinoline, 129–130 blockers of, 328 furosemide, 328 Na2+/2Cl–/K+ carrier, 328 R , 328 Ralfinamide, 97 torasemide, 329 , 99–100 triflocine, 329 Recognition, 59, 64 Index 347

Remacemide, 101 (TTX), 70, 85, 95, 101, 103 retro-QSAR, 261 Thalamic rhythm, 39 Root-mean-square fluctuations (RMSF), 62 Thermodynamics, 57, 61, 63, 66–68 RSD1235, 101 1,2,4-Thiadiazines, 61 Ryanodine receptor (RyR), 69 Thiazolidinone, 123–125 Thyrotoxicosis, 45 , 67 S , 94, 96, 98, 101, 102 Safinamide, 101 TOPP, 61 SAN. See Sinoatrial node Torsades de pointes (Tdp), 120, 132, 139 SAR. See Structure activity relationships description, 158–159 Schizophrenia, 55 drug-induced QT prolongation, 160–163 Scoring function, 58, 63, 65 Transmembrane domains, 316 Sertindole, 58, 63 Transmembrane helical (TMH) proteins SHAKE, 65 features, 4 Shaker, 60 spanning region prediction Sinoatrial node (SAN), 34, 37, 39, 40, 42, 44 HMM, 6–7 Sinus rhythm (SR), 138–139 machine-learning methods, 7 Spermine, 59 multiple sequence alignment, 7 STERIMOL parameters, 255 statistical methods, 5–6 Structural discrimination, membrane proteins Web servers, 8 b-barrel membrane proteins, 9–13 Transmembrane strand (TMS) proteins spanning b-strand segments, 13–17 rules, 8–9 TMH proteins, 4–8 Web servers, 12 TMS proteins, 8–9 Transporter Classification Database (TCDB), Structure activity relationships (SAR), 18–19 272–278 Transporters, membrane proteins Structure-based approaches based on different classes and families, amino acids involvement, 220–222 23–25 binding affinity model, 225–226 from globular proteins, 21 binding interactions, 225 Triarylethanolamine, 136 docking results, 229–232 Tripos force field, 61 docking studies, 227–228 TTX. See Tetrodotoxin drug trapping, 218–220 Gly648 role, 223 homology models, 217–218 V hydrogen bonds with Thr623, Ser624 and Validation, 62–63 Val625, 222–223 Ventricular effective refractory period orthogonal binding site, 229 (VERP), 122, 124, 126, 129 para-substituents influence on phenyl ring, , 101, 138 224–225 VERP. See Ventricular effective refractory subunits involvement, 223–224 period Subunits, 83, 85–91 VGSCs. See Voltage-gated sodium channels a, 82–88, 98, 119 VolSurf procedure, 61 b, 82–83, 86, 87, 89, 101, 119 Voltage dependent Ca2+, 266 Voltage-gated channels, 243 Voltage-gated potassium channel (Kv), 56 T Kv1, 63 Tdp. See Torsades de pointes Kv1.3, 57, 60, 63 , 139–140 Kv1.5, 59, 63, 64 Tetrahydroindolone, 125–126 KvAP channel, 62 Tetrahydronaphthyls, 126–127, 130 Voltage-gated sodium channels (VGSCs), 67 Tetrazole, 123–125 Voltage sensing domains (VSDs), 155 348 Index

W Y Wannier functions, 70 Yanoguanidines, 61 Weighted holistic invariant molecular (WHIM) descriptors, 254 Z Zatebradine, 41–43 X ZD 7288, 41, 45–46 Xenopus oocytes, 249 , 94, 102