Molecular Drug targets
Molecular Drug Targets

Molecular Drug targets
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Calcium channels as drug targets.

Voltage-gated calcium channels are key players in muscle contraction, hormone and neurotransmitter release, and regulation of gene transcription. Calcium channels blockers (e.g. 1,4-dihydropyridines, phenylalkylamines, diltiazem and mibefradil) exert their antiarrhythmic and antihypertensive action by restricting Ca2+ entry into myocardial and smooth muscle cells.

The molecular mechanisms of calcium channel inhibition and channel recovery are the focus of this project. We will make use of mutations shifting channel gating to answer basic questions such as whether the access of different channel blockers to their binding pockets and recovery from block are voltage dependent and how inactivation modulates channel block.

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Investigation on the influence of the expression system on the sodium channel response.

Preliminary data obtained with a sodium channel blocking agent on native and in oocytes expressed cardiac and neuronal sodium channels showed a dependency of the test compound’s effect on the subtype of native sodium channels, which are differently expressed in various excitable tissues. Thus, it is intended to study the effect of sodium-channel affecting compounds in different expression systems in order to find the reason for this discrepancy. The subtype channel dependent mechanism of action is of interest and importance regarding the interpretation of results obtained from distinct screening tests. For this purpose cardiac and neuronal sodium channels will be expressed in different expression systems, and the sodium current will be measured by means of electrophysiological techniques.

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Quantification of HERG channel block.

State dependent block of HERG channels can be described by i) drug association with open channels; ii) dissociation from open channels and iii) dissociation from the closed (drug trapping) HERG channel state. The aim of the project is to estimate the apparent rate constants of these processes (indices enabling prediction of the amount of block at a given pulse protocol). HERG channel inhibition will be analyzed at different pulse lengths, frequencies and drug concentrations. Mutant channels will be utilized to elucidate the role of the molecular determinants of channel-drug interaction.

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Virtual and real screening of natural products to find effective modulators of protein tyrosine phosphatase PTP1B.

The project resides in the field of molecular pharmacology of natural products. Special focus lies on the identification and mechanistic investigation of compounds that protect against insulin resistance and subsequent cardiovascular complications seen in metabolic syndrome and type II diabetes. For the proposed studies, the protein tyrosine phosphatase (PTP) PTP1B, a negative regulator of insulin signalling, will be taken as central (inhibitable) target: Starting from an “in silico” screening of a database of natural compounds, promising candidates for PTP1B inhibition will be validated in in vitro enzymatic assays as well as cell-based models for e.g. endothelial insulin resistance. Thus, after a successful set up of the in vitro assay, the graduate student will gain knowledge in cultivating primary cells and cell lines as well as in state of the art cell biological methods such as RT-PCR, western blotting, flow cytometry and siRNA technology.

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Isolation of modulators of ligand and voltage gated ion channels from natural origin.

Herbal medicinal products with sedative effects have long been used both in folk medicine and phytotherapy. Herbal products will be extracted making use of modern technologies and their action will be analysed on heterologously expressed receptors such as GABAA and voltage gated channels. Currents througth ion channels will be measured with the Two-Microelectrode Voltage-Clamp and Patch Clamp Technique. The final aim is to identify substances from herbal extracts with activity on GABAA and other ion channels.

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In silico screening on the HERG potassium channel.

Almost 35 % of all compounds in the drug development pipeline fail due to improper ADMET properties. The hERG potassium channel represents an important part of the cardiac action potential. Undesirable blockade of the hERG channel results in potentially life-threatening arrhythmias and was at least in part responsible for the withdrawal of several drugs from the market. This project aims at the development of suitable algorithms for in silico screening of large compound libraries in order to identify hERG ligands. Main methods to be applied include our recently developed SIBAR-descriptors. These are based on calculation of similarity values between compounds of the training set and an external reference set. Subsequently these similarity values will be used as input vector for linear (PLS) and non-linear regression analyses. Studies will be complemented by structure-based design techniques.

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Investigation of chondroprotective effects with the aid of miniaturized cell culture arrays.

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Interaction determinants between pore regions and voltage sensors in calcium channels.

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Subunit dependent pharmacology of GABAA-receptors.

This study aims to get insight in the pharmacological properties of receptor subtype composed of a-, b- and g1-subunits. Whereas the pharmacology of a1b2g2S-receptors has been in the focus of most previously performed studies little is known about a1b2g1-receptors. The limited expression of g1 in certain areas of the central nervous system (i.e. amygdala, pallidum, centrolateral and medial nuclei of the thalamus, substantia nigra) provides the possibility to modulate selectively these brain regions. In order to establish potent and efficient modulators of a1b2g1-receptors a compound library will be investigated. Promising - i.e. highly potent and highly efficient compounds - will be selected for further more detailed studies and their subunit specific action studied on other GABAA-receptor isoforms.

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Structure-function analysis of the mitochondrial Mg2+ channel protein MRS2.

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Molecular Drug targets
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