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152. Structure–Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1)

Author

Jørgensen, Lars, Al-Khawaja, Anas, Kickinger, Stefanie, Vogensen, Stine B., Skovgaard-Petersen, Jonas, Rosenthal, Emil, Borkar, Nrupa, Löffler, Rebekka, Madsen, Karsten K., Bräuner-Osborne, Hans, Schousboe, Arne, Ecker, Gerhard F., Wellendorph, Petrine, and Clausen, Rasmus P.

Abstract

N-(1-Benzyl-4-piperidinyl)-2,4-dichlorobenzamide 5(BPDBA) is a noncompetitive inhibitor of the betaine/GABA transporter 1 (BGT1). We here report the synthesis and structure–activity relationship of 71 analogues. We identify 26mas a more soluble 2,4-Cl substituted 3-pyridine analogue with retained BGT1 activity and an improved off-target profile compared to 5. We performed radioligand-based uptake studies at chimeric constructs between BGT1 and GAT3, experiments with site-directed mutated transporters, and computational docking in a BGT1 homology model based on the newly determined X-ray crystal structure of the human serotonin transporter (hSERT). On the basis of these experiments, we propose a binding mode involving residues within TM10 in an allosteric site in BGT1 that corresponds to the allosteric binding pocket revealed by the hSERT crystal structure. Our study provides first insights into a proposed allosteric binding pocket in BGT1, which accommodates the binding site for a series of novel noncompetitive inhibitors.

Published
2024
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153. Flagging Drugs That Inhibit the Bile Salt Export Pump

Author

Montanari, Floriane, Pinto, Marta, Khunweeraphong, Narakorn, Wlcek, Katrin, Sohail, M Imran, Noeske, Tobias, Boyer, Scott, Chiba, Peter, Stieger, Bruno, Kuchler, Karl, Ecker, Gerhard F, Montanari, Floriane, Pinto, Marta, Khunweeraphong, Narakorn, Wlcek, Katrin, Sohail, M Imran, Noeske, Tobias, Boyer, Scott, Chiba, Peter, Stieger, Bruno, Kuchler, Karl, and Ecker, Gerhard F

Abstract

The bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepatocytes. Its physiological role is to expel bile salts into the canaliculi from where they drain into the bile duct. Inhibition of this transporter may lead to intrahepatic cholestasis. Predictive computational models of BSEP inhibition may allow for fast identification of potentially harmful compounds in large databases. This article presents a predictive in silico model based on physicochemical descriptors that is able to flag compounds as potential BSEP inhibitors. This model was built using a training set of 670 compounds with available BSEP inhibition potencies. It successfully predicted BSEP inhibition for two independent test sets and was in a further step used for a virtual screening experiment. After in vitro testing of selected candidates, a marketed drug, bromocriptin, was identified for the first time as BSEP inhibitor. This demonstrates the usefulness of the model to identify new BSEP inhibitors and therefore potential cholestasis perpetrators.

Published
2016

157. Characterization of Mephedrone and its Bioactive Metabolites

Author

Mayer, Felix P, primary, Partilla, John S, additional, Wimmer, Laurin, additional, Seddik, Amir, additional, Burchardt, Nadine, additional, Schmid, Diethart, additional, Bulling, Simon, additional, Ecker, Gerhard F, additional, Mihovilovic, Marko D, additional, Baumann, Michael H, additional, and Sitte, Harald H, additional

Published
2016
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159. Amphetamine actions at the serotonin transporter rely on the availability of phosphatidylinositol-4,5-bisphosphate

Author

Buchmayer, Florian, Schicker, Klaus, Steinkellner, Thomas, Geier, Petra, Stübiger, Gerald, Hamilton, Peter J., Jurik, Andreas, Stockner, Thomas, Yang, Jae-Won, Montgomery, Therese, Holy, Marion, Hofmaier, Tina, Kudlacek, Oliver, Matthies, Heinrich J. G., Ecker, Gerhard F., Bochkov, Valery, Galli, Aurelio, Boehm, Stefan, and Sitte, Harald H.

Subjects
Phosphatidylinositol 4,5-Diphosphate, Serotonin Plasma Membrane Transport Proteins, Amphetamine, HEK293 Cells, Humans, lipids (amino acids, peptides, and proteins), Biological Sciences, Second Messenger Systems
Abstract

Nerve functions require phosphatidylinositol-4,5-bisphosphate (PIP2) that binds to ion channels, thereby controlling their gating. Channel properties are also attributed to serotonin transporters (SERTs); however, SERT regulation by PIP2 has not been reported. SERTs control neurotransmission by removing serotonin from the extracellular space. An increase in extracellular serotonin results from transporter-mediated efflux triggered by amphetamine-like psychostimulants. Herein, we altered the abundance of PIP2 by activating phospholipase-C (PLC), using a scavenging peptide, and inhibiting PIP2-synthesis. We tested the effects of the verified scarcity of PIP2 on amphetamine-triggered SERT functions in human cells. We observed an interaction between SERT and PIP2 in pull-down assays. On decreased PIP2 availability, amphetamine-evoked currents were markedly reduced compared with controls, as was amphetamine-induced efflux. Signaling downstream of PLC was excluded as a cause for these effects. A reduction of substrate efflux due to PLC activation was also found with recombinant noradrenaline transporters and in rat hippocampal slices. Transmitter uptake was not affected by PIP2 reduction. Moreover, SERT was revealed to have a positively charged binding site for PIP2. Mutation of the latter resulted in a loss of amphetamine-induced SERT-mediated efflux and currents, as well as a lack of PIP2-dependent effects. Substrate uptake and surface expression were comparable between mutant and WT SERTs. These findings demonstrate that PIP2 binding to monoamine transporters is a prerequisite for amphetamine actions without being a requirement for neurotransmitter uptake. These results open the way to target amphetamine-induced SERT-dependent actions independently of normal SERT function and thus to treat psychostimulant addiction.

Published
2013

160. Mutational analysis of the high-affinity zinc binding site validates a refined human dopamine transporter homology model

Author

Stockner, Thomas, Montgomery, Therese R., Kudlacek, Oliver, Weissensteiner, Rene, Ecker, Gerhard F., Freissmuth, Michael, and Sitte, Harald H.

Subjects
Models, Molecular, 1-Methyl-4-phenylpyridinium, Protein Structure, Drugs and Devices, QH301-705.5, Protein Conformation, Psychopharmacology, DNA Mutational Analysis, Molecular Sequence Data, Neuropharmacology, Chlorides, Recreational Drug Use, Macromolecular Structure Analysis, Biochemical Simulations, Humans, Histidine, Cysteine, Amino Acid Sequence, Biology (General), Biology, Drug Dependence, Dopamine Plasma Membrane Transport Proteins, Binding Sites, Water, Computational Biology, Parkinson Disease, Neurotransmitters, Dopamine transporters, Simulation and modeling, Protein Structure, Tertiary, Salt bridges, Zinc, HEK293 Cells, Neurology, Behavioral Pharmacology, Medicine, Biophysic Al Simulations, Sequence Alignment, Protein Binding, Research Article, Neuroscience
Abstract

The high-resolution crystal structure of the leucine transporter (LeuT) is frequently used as a template for homology models of the dopamine transporter (DAT). Although similar in structure, DAT differs considerably from LeuT in a number of ways: (i) when compared to LeuT, DAT has very long intracellular amino and carboxyl termini; (ii) LeuT and DAT share a rather low overall sequence identity (22%) and (iii) the extracellular loop 2 (EL2) of DAT is substantially longer than that of LeuT. Extracellular zinc binds to DAT and restricts the transporter‚s movement through the conformational cycle, thereby resulting in a decrease in substrate uptake. Residue H293 in EL2 praticipates in zinc binding and must be modelled correctly to allow for a full understanding of its effects. We exploited the high-affinity zinc binding site endogenously present in DAT to create a model of the complete transmemberane domain of DAT. The zinc binding site provided a DAT-specific molecular ruler for calibration of the model. Our DAT model places EL2 at the transporter lipid interface in the vicinity of the zinc binding site. Based on the model, D206 was predicted to represent a fourth co-ordinating residue, in addition to the three previously described zinc binding residues H193, H375 and E396. This prediction was confirmed by mutagenesis: substitution of D206 by lysine and cysteine affected the inhibitory potency of zinc and the maximum inhibition exerted by zinc, respectively. Conversely, the structural changes observed in the model allowed for rationalizing the zinc-dependent regulation of DAT: upon binding, zinc stabilizes the outward-facing state, because its first coordination shell can only be completed in this conformation. Thus, the model provides a validated solution to the long extracellular loop and may be useful to address other aspects of the transport cycle., Author Summary The dopamine transporter (DAT) regulates dopaminergic neurotransmission in the brain and is implicated in numerous human disease states. DAT is unique among the monoamine neurotransmitter transporter family because its substrate transport is inhibited by extracellular zinc. DAT homology models rely upon the crystal structure of LeuT solved in 2005. LeuT and DAT share a relatively low overall sequence identity of 22%. In addition, the length of the second extracellular loop of DAT exceeds that of LeuT by 21 residues. The zinc binding site cannot be directly modeled from the LeuT template alone because of these differences. Current available homology models of DAT focused on substrate or inhibitor binding rather than on the second extracellular loop. We exploited the specificity of the zinc binding site to build and calibrate a DAT homology model of the complete transmembrane domain. Our model predicted that the zinc binding site in DAT consists of four zinc co-ordinating residues rather than three that had been previously identified. We verified this hypothesis by site-directed mutagenesis and uptake inhibition studies.

Published
2012

161. Exhaustive sampling of docking poses reveals binding hypotheses for propafenone type inhibitors of P-glycoprotein

Author

Klepsch, Freya, Chiba, Peter, and Ecker, Gerhard F.

Subjects
Models, Molecular, Protein Structure, Drugs and Devices, Drug Research and Development, Biochemistry, Computer Applications, DRUG-BINDING, Transmembrane Transport Proteins, Mice, Structure-Activity Relationship, ABC TRANSPORTERS, SUBSTRATE, Propafenone, MOLECULAR-BASIS, Drug Discovery, Macromolecular Structure Analysis, Animals, Cluster Analysis, Humans, Drug Interactions, ATP Binding Cassette Transporter, Subfamily B, Member 1, Amino Acid Sequence, MULTIDRUG-RESISTANCE, Biology, lcsh:QH301-705.5, LEAD IDENTIFICATION, Binding Sites, DOMAIN/TRANSMEMBRANE DOMAIN INTERFACES, Proteins, Computational Biology, SITE, Transmembrane Proteins, Chemistry, MODULATORS, lcsh:Biology (General), Small Molecules, Structural Homology, Protein, Computer Science, LIGAND-BINDING, Computer-Aided Design, Medicine, Medicinal Chemistry, Research Article, Protein Binding
Abstract

Overexpression of the xenotoxin transporter P-glycoprotein (P-gp) represents one major reason for the development of multidrug resistance (MDR), leading to the failure of antibiotic and cancer therapies. Inhibitors of P-gp have thus been advocated as promising candidates for overcoming the problem of MDR. However, due to lack of a high-resolution structure the concrete mode of interaction of both substrates and inhibitors is still not known. Therefore, structure-based design studies have to rely on protein homology models. In order to identify binding hypotheses for propafenone-type P-gp inhibitors, five different propafenone derivatives with known structure-activity relationship (SAR) pattern were docked into homology models of the apo and the nucleotide-bound conformation of the transporter. To circumvent the uncertainty of scoring functions, we exhaustively sampled the pose space and analyzed the poses by combining information retrieved from SAR studies with common scaffold clustering. The results suggest propafenone binding at the transmembrane helices 5, 6, 7 and 8 in both models, with the amino acid residue Y307 playing a crucial role. The identified binding site in the non-energized state is overlapping with, but not identical to, known binding areas of cyclic P-gp inhibitors and verapamil. These findings support the idea of several small binding sites forming one large binding cavity. Furthermore, the binding hypotheses for both catalytic states were analyzed and showed only small differences in their protein-ligand interaction fingerprints, which indicates only small movements of the ligand during the catalytic cycle., Author Summary A major reason for the failure of cancer, antibiotic and antiviral therapies is the development of multidrug resistance (MDR). P-glycoprotein (P-gp), an ATP-dependent transport protein located in the membrane of epithelial cells of the kidney, liver, pancreas, colon and the blood-brain barrier, has been linked to the export of a broad variety of xenotoxins. Overexpression of P-gp leads to extrusion of therapeutic drugs and therefore triggers MDR. Thus, identification of potential P-gp inhibitors represents a promising concept for treatment of multiresistant tumours. However, due to lack of high resolution structural information and the polyspecific ligand recognition pattern only very limited information is available on the molecular basis of ligand/transporter interaction. Within this study we characterized the propafenone binding site of P-gp by docking a set of derivatives with known SAR into homology models of P-gp which represent both the apo and the nucleotide-bound state. Poses retrieved are in accordance with results from previous photoaffinity labeling studies and thus pave the way for structure-based in silico screening approaches.

Published
2011

162. Flagging Drugs That Inhibit the Bile Salt Export Pump

Author

Montanari, Floriane, primary, Pinto, Marta, additional, Khunweeraphong, Narakorn, additional, Wlcek, Katrin, additional, Sohail, M. Imran, additional, Noeske, Tobias, additional, Boyer, Scott, additional, Chiba, Peter, additional, Stieger, Bruno, additional, Kuchler, Karl, additional, and Ecker, Gerhard F., additional

Published
2015
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164. Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters

Author

Sandtner, Walter, primary, Stockner, Thomas, additional, Hasenhuetl, Peter S., additional, Partilla, John S., additional, Seddik, Amir, additional, Zhang, Yuan-Wei, additional, Cao, Jianjing, additional, Holy, Marion, additional, Steinkellner, Thomas, additional, Rudnick, Gary, additional, Baumann, Michael H., additional, Ecker, Gerhard F., additional, Newman, Amy Hauck, additional, and Sitte, Harald H., additional

Published
2015
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165. Identification of the First Highly Subtype-Selective Inhibitor of Human GABA Transporter GAT3

Author

Damgaard, Maria, primary, Al-Khawaja, Anas, additional, Vogensen, Stine B., additional, Jurik, Andreas, additional, Sijm, Maarten, additional, Lie, Maria E. K., additional, Bæk, Mathias I., additional, Rosenthal, Emil, additional, Jensen, Anders A., additional, Ecker, Gerhard F., additional, Frølund, Bente, additional, Wellendorph, Petrine, additional, and Clausen, Rasmus P., additional

Published
2015
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166. Integrative Modeling Strategies for Predicting Drug Toxicities at the eTOX Project

Author

Sanz, Ferran, primary, Carrió, Pau, additional, López, Oriol, additional, Capoferri, Luigi, additional, Kooi, Derk P., additional, Vermeulen, Nico P. E., additional, Geerke, Daan P., additional, Montanari, Floriane, additional, Ecker, Gerhard F., additional, Schwab, Christof H., additional, Kleinöder, Thomas, additional, Magdziarz, Tomasz, additional, and Pastor, Manuel, additional

Published
2015
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169. Passive Lipoidal Diffusion and Carrier-Mediated Cell Uptake Are Both Important Mechanisms of Membrane Permeation in Drug Disposition

Author

Smith, Dennis, Artursson, Per, Avdeef, Alex, Di, Li, Ecker, Gerhard F., Faller, Bernard, Houston, J. Brian, Kansy, Manfred, Kerns, Edward H., Kramer, Stefanie D., Lennernäs, Hans, van de Waterbeemd, Han, Sugano, Kiyohiko, Testa, Bernard, Smith, Dennis, Artursson, Per, Avdeef, Alex, Di, Li, Ecker, Gerhard F., Faller, Bernard, Houston, J. Brian, Kansy, Manfred, Kerns, Edward H., Kramer, Stefanie D., Lennernäs, Hans, van de Waterbeemd, Han, Sugano, Kiyohiko, and Testa, Bernard

Abstract

Recently, it has been proposed that drug permeation is essentially carrier-mediated only and that passive lipoidal diffusion is negligible. This opposes the prevailing hypothesis of drug permeation through biological membranes, which integrates the contribution of multiple permeation mechanisms, including both carrier-mediated and passive lipoidal diffusion, depending on the compound's properties, membrane properties, and solution properties. The prevailing hypothesis of drug permeation continues to be successful for application and prediction in drug development. Proponents of the carrier-mediated only concept argue against passive lipoidal diffusion. However, the arguments are not supported by broad pharmaceutics literature. The carrier-mediated only concept lacks substantial supporting evidence and successful applications in drug development.

Published
2014
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171. Combined Simulation and Mutation Studies to Elucidate Selectivity of Unsubstituted Amphetamine-like Cathinones at the Dopamine Transporter.

Author

Seddik, Amir, Geerke, Daan P., Stockner, Thomas, Holy, Marion, Kudlacek, Oliver, Cozzi, Nicholas V., Ruoho, Arnold E., Sitte, Harald H., and Ecker, Gerhard F.

Subjects
DOPAMINE, MENTAL illness, AMPHETAMINES
Abstract

The dopamine and serotonin transporter proteins (DAT, SERT) play a vital role in behavior and mental illness. Although their substrate transport has been studied extensively, the molecular basis of their selectivity is not completely understood yet. In this study, we exploit molecular dynamics simulations combined with mutagenesis studies to shed light on the driving factors for DAT-over-SERT selectivity of a set of cathinones. Results indicate that these compounds can adopt two binding modes of which one is more favorable. In addition, free energy calculations indicated the substrate binding site (S1) as the primary recognition site for these ligands. By simulating DAT with SERT-like mutations, we hypothesize unsubstituted cathinones to bind more favorably to DAT, due to a Val152 offering more space, as compared to the bulkier Ile172 in SERT. This was supported by uptake inhibition measurements, which showed an increase in activity in SERT-I172V. [ABSTRACT FROM AUTHOR]

Published
2017
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172. Virtual Screening of DrugBank Reveals Two Drugs as New BCRP Inhibitors.

Author

Montanari, Floriane, Cseke, Anna, Wlcek, Katrin, and Ecker, Gerhard F.

Abstract

The breast cancer resistance protein (BCRP) is an ABC transporter playing a crucial role in the pharmacokinetics of drugs. The early identification of substrates and inhibitors of this efflux transporter can help to prevent or foresee drug-drug interactions. In this work, we built a ligand-based in silico classification model to predict the inhibitory potential of drugs toward BCRP. The model was applied as a virtual screening technique to identify potential inhibitors among the small-molecules subset of DrugBank. Ten compounds were selected and tested for their capacity to inhibit mitoxantrone efflux in BCRP-expressing PLB985 cells. Results identified cisapride (IC50 = 0.4 µM) and roflumilast (IC50 = 0.9 µM) as two new BCRP inhibitors. The in silico strategy proved useful to prefilter potential drug-drug interaction perpetrators among a database of small molecules and can reduce the amount of compounds to test. [ABSTRACT FROM AUTHOR]

Published
2017
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174. The Application of the Open Pharmacological Concepts Triple Store (Open PHACTS) to Support Drug Discovery Research

Author

Ratnam, Joseline, primary, Zdrazil, Barbara, additional, Digles, Daniela, additional, Cuadrado-Rodriguez, Emiliano, additional, Neefs, Jean-Marc, additional, Tipney, Hannah, additional, Siebes, Ronald, additional, Waagmeester, Andra, additional, Bradley, Glyn, additional, Chau, Chau Han, additional, Richter, Lars, additional, Brea, Jose, additional, Evelo, Chris T., additional, Jacoby, Edgar, additional, Senger, Stefan, additional, Loza, Maria Isabel, additional, Ecker, Gerhard F., additional, and Chichester, Christine, additional

Published
2014
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178. Efficient Modulation of γ-Aminobutyric Acid Type A Receptors by Piperine Derivatives

Author

Schöffmann, Angela, primary, Wimmer, Laurin, additional, Goldmann, Daria, additional, Khom, Sophia, additional, Hintersteiner, Juliane, additional, Baburin, Igor, additional, Schwarz, Thomas, additional, Hintersteininger, Michael, additional, Pakfeifer, Peter, additional, Oufir, Mouhssin, additional, Hamburger, Matthias, additional, Erker, Thomas, additional, Ecker, Gerhard F., additional, Mihovilovic, Marko D., additional, and Hering, Steffen, additional

Published
2014
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182. Passive Lipoidal Diffusion and Carrier-Mediated Cell Uptake Are Both Important Mechanisms of Membrane Permeation in Drug Disposition

Author

Smith, Dennis, primary, Artursson, Per, additional, Avdeef, Alex, additional, Di, Li, additional, Ecker, Gerhard F., additional, Faller, Bernard, additional, Houston, J. Brian, additional, Kansy, Manfred, additional, Kerns, Edward H., additional, Krämer, Stefanie D., additional, Lennernäs, Hans, additional, van de Waterbeemd, Han, additional, Sugano, Kiyohiko, additional, and Testa, Bernard, additional

Published
2014
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187. Scientific competency questions as the basis for semantically enriched open pharmacological space development

Author

Azzaoui, Kamal, Jacoby, Edgar, Senger, Stefan, Rodríguez, Emiliano Cuadrado, Loza, Mabel, Zdrazil, Barbara, Pinto, Marta, Williams, Antony J., de la Torre, Victor, Mestres, Jordi, Pastor, Manuel, Taboureau, Olivier, Rarey, Matthias, Chichester, Christine, Pettifer, Steve, Blomberg, Niklas, Harland, Lee, Williams-Jones, Bryn, Ecker, Gerhard F., Azzaoui, Kamal, Jacoby, Edgar, Senger, Stefan, Rodríguez, Emiliano Cuadrado, Loza, Mabel, Zdrazil, Barbara, Pinto, Marta, Williams, Antony J., de la Torre, Victor, Mestres, Jordi, Pastor, Manuel, Taboureau, Olivier, Rarey, Matthias, Chichester, Christine, Pettifer, Steve, Blomberg, Niklas, Harland, Lee, Williams-Jones, Bryn, and Ecker, Gerhard F.

Abstract

Molecular information systems play an important part in modern data-driven drug discovery. They do not only support decision making but also enable new discoveries via association and inference. In this review, we outline the scientific requirements identified by the Innovative Medicines Initiative (IMI) Open PHACTS consortium for the design of an open pharmacological space (OPS) information system. The focus of this work is the integration of compound–target–pathway–disease/phenotype data for public and industrial drug discovery research. Typical scientific competency questions provided by the consortium members will be analyzed based on the underlying data concepts and associations needed to answer the questions. Publicly available data sources used to target these questions as well as the need for and potential of semantic web-based technology will be presented.

Published
2013

190. Coexistence of passive and carrier-mediated processes in drug transport

Author

Sugano, Kiyohiko, Kansy, Manfred, Artursson, Per, Avdeef, Alex, Bendels, Stefanie, Di, Li, Ecker, Gerhard F, Faller, Bernard, Fischer, Holger, Gerebtzoff, Grégori, Lennernäs, Hans, Senner, Frank, Sugano, Kiyohiko, Kansy, Manfred, Artursson, Per, Avdeef, Alex, Bendels, Stefanie, Di, Li, Ecker, Gerhard F, Faller, Bernard, Fischer, Holger, Gerebtzoff, Grégori, Lennernäs, Hans, and Senner, Frank

Abstract

The permeability of biological membranes is one of the most important determinants of the pharmacokinetic processes of a drug. Although it is often accepted that many drug substances are transported across biological membranes by passive transcellular diffusion, a recent hypothesis speculated that carrier-mediated mechanisms might account for the majority of membrane drug transport processes in biological systems. Based on evidence of the physicochemical characteristics and of in vitro and in vivo findings for marketed drugs, as well as results from real-life discovery and development projects, we present the view that both passive transcellular processes and carrier-mediated processes coexist and contribute to drug transport activities across biological membranes.

Published
2010
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192. Scientific competency questions as the basis for semantically enriched open pharmacological space development

Author

Azzaoui, Kamal, primary, Jacoby, Edgar, additional, Senger, Stefan, additional, Rodríguez, Emiliano Cuadrado, additional, Loza, Mabel, additional, Zdrazil, Barbara, additional, Pinto, Marta, additional, Williams, Antony J., additional, de la Torre, Victor, additional, Mestres, Jordi, additional, Pastor, Manuel, additional, Taboureau, Olivier, additional, Rarey, Matthias, additional, Chichester, Christine, additional, Pettifer, Steve, additional, Blomberg, Niklas, additional, Harland, Lee, additional, Williams-Jones, Bryn, additional, and Ecker, Gerhard F., additional

Published
2013
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193. Amphetamine actions at the serotonin transporter rely on the availability of phosphatidylinositol-4,5-bisphosphate

Author

Buchmayer, Florian, primary, Schicker, Klaus, additional, Steinkellner, Thomas, additional, Geier, Petra, additional, Stübiger, Gerald, additional, Hamilton, Peter J., additional, Jurik, Andreas, additional, Stockner, Thomas, additional, Yang, Jae-Won, additional, Montgomery, Therese, additional, Holy, Marion, additional, Hofmaier, Tina, additional, Kudlacek, Oliver, additional, Matthies, Heinrich J. G., additional, Ecker, Gerhard F., additional, Bochkov, Valery, additional, Galli, Aurelio, additional, Boehm, Stefan, additional, and Sitte, Harald H., additional

Published
2013
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195. Identification of novel positive allosteric modulators and null modulators at the GABAAreceptor α+β− interface

Author

Varagic, Zdravko, primary, Wimmer, Laurin, additional, Schnürch, Michael, additional, Mihovilovic, Marko D, additional, Huang, Shengming, additional, Rallapalli, Sundari, additional, Cook, James M, additional, Mirheydari, Pantea, additional, Ecker, Gerhard F, additional, Sieghart, Werner, additional, and Ernst, Margot, additional

Published
2013
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198. Experimental characterization of the human non-sequence-specific nucleic acid interactome

Author

Dürnberger, Gerhard, primary, Bürckstümmer, Tilmann, additional, Huber, Kilian, additional, Giambruno, Roberto, additional, Doerks, Tobias, additional, Karayel, Evren, additional, Burkard, Thomas R, additional, Kaupe, Ines, additional, Müller, André C, additional, Schönegger, Andreas, additional, Ecker, Gerhard F, additional, Lohninger, Hans, additional, Bork, Peer, additional, Bennett, Keiryn L, additional, Superti-Furga, Giulio, additional, and Colinge, Jacques, additional

Published
2013
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199. Selectivity profiling of BCRP versus P-gp inhibition: from automated collection of polypharmacology data to multi-label learning.

Author

Montanari, Floriane, Zdrazil, Barbara, Digles, Daniela, and Ecker, Gerhard F.

Subjects
MULTIDRUG resistance, BREAST cancer treatment, ATP-binding cassette transporters, PHARMACOKINETICS, DRUG development, PROTEIN expression
Abstract

Background: The human ATP binding cassette transporters Breast Cancer Resistance Protein (BCRP) and Multidrug Resistance Protein 1 (P-gp) are co-expressed in many tissues and barriers, especially at the blood-brain barrier and at the hepatocyte canalicular membrane. Understanding their interplay in affecting the pharmacokinetics of drugs is of prime interest. In silico tools to predict inhibition and substrate profiles towards BCRP and P-gp might serve as early filters in the drug discovery and development process. However, to build such models, pharmacological data must be collected for both targets, which is a tedious task, often involving manual and poorly reproducible steps. Results: Compounds with inhibitory activity measured against BCRP and/or P-gp were retrieved by combining Open Data and manually curated data from literature using a KNIME workflow. After determination of compound overlap, machine learning approaches were used to establish multi-label classification models for BCRP/P-gp. Different ways of addressing multi-label problems are explored and compared: label-powerset, binary relevance and classifiers chain. Label-powerset revealed important molecular features for selective or polyspecific inhibitory activity. In our dataset, only two descriptors (the numbers of hydrophobic and aromatic atoms) were sufficient to separate selective BCRP inhibitors from selective P-gp inhibitors. Also, dual inhibitors share properties with both groups of selective inhibitors. Binary relevance and classifiers chain allow improving the predictivity of the models. Conclusions: The KNIME workflow proved a useful tool to merge data from diverse sources. It could be used for building multi-label datasets of any set of pharmacological targets for which there is data available either in the open domain or in-house. By applying various multi-label learning algorithms, important molecular features driving transporter selectivity could be retrieved. Finally, using the dataset with missing annotations, predictive models can be derived in cases where no accurate dense dataset is available (not enough data overlap or no well balanced class distribution). [ABSTRACT FROM AUTHOR]

Published
2016
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200. Development of Refined Homology Models: Adding the Missing Information to the Medically Relevant Neurotransmitter Transporters.

Author

Stockner, Thomas, Jurik, Andreas, Weissensteiner, René, Freissmuth, Michael, Ecker, Gerhard F., and Sitte, Harald H.

Abstract

Neurotransmitter:sodium symporters are located on presynaptic neurons and terminate neurotransmission by removing the monoamine substrates from the synaptic cleft. Until very recently, only several conformational snapshots/structures of a bacterial homolog of neurotransmitter:sodium symporters, namely, the leucine/alanine transporter LeuT from Aquifex aeolicus, were available. However, this transporter shares only 21b % overall sequence identity with its human homologs. In this chapter, we describe how a model can be developed from a template with such low identity. The effort of model building will strongly depend on the purpose. We discuss this process and focus on the important steps that allowed us to obtain a model which can be used for molecular dynamics simulations. Furthermore, we also highlight the inherent limitations of the proposed approaches. Prediction of ligand binding brings in additional complexity. Therefore, experimental scrutiny of the resulting models is a key component to successful validation. We describe two specific examples: model building of the dopamine transporter and ligand docking to the serotonin transporter. We evaluate our modeling approach by direct comparison of our models to the recently published first eukaryotic neurotransmitter:sodium symporter, the drosophila melanogaster DAT transporter. [ABSTRACT FROM AUTHOR]

Published
2014
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