Karsten Andrae

Dynamic covalent hydrazine chemistry as a selective extraction and cleanup technique for the quantification of the Fusarium mycotoxin zearalenone in edible oils.

A novel, cost-efficient method for the analytical extraction of the Fusarium mycotoxin zearalenone (ZON) from edible oils by dynamic covalent hydrazine chemistry (DCHC) was developed and validated for its application with high performance liquid chromatography-fluorescence detection (HPLC-FLD). ZON is extracted from the edible oil by hydrazone formation on a polymer resin functionalised with hydrazine groups and subsequently released by hydrolysis. Specifity and precision of this approach are superior to liquid partitioning or gel permeation chromatography (GPC). DCHC also extracts zearalanone (ZAN) but not alpha-/beta-zearalenol or -zearalanol. The hydrodynamic properties of ZON, which were estimated using molecular simulation data, indicate that the compound is unaffected by nanofiltration through the resin pores and thus selectively extracted. The methods levels of detection and quantification are 10 and 30 microg/kg, using 0.2g of sample. Linearity is given in the range of 10-20,000 microg/kg, the average recovery being 89%. Bias and relative standard deviations do not exceed 7%. In a sample survey of 44 commercial edible oils based on various agricultural commodities (maize, olives, nuts, seeds, etc.) ZON was detected in four maize oil samples, the average content in the positive samples being 99 microg/kg. The HPLC-FLD results were confirmed by HPLC-tandem mass spectrometry and compared to those obtained by a liquid partitioning based sample preparation procedure.

Investigation of the Ergopeptide Epimerization Process

Ergopeptides, like ergocornine and a-ergocryptine, exist in an S- and in an R-configuration. Kinetic experiments imply that certain configurations are preferred depending on the solvent. The experimental methods are explained in this article. Furthermore, computational methods are used to understand this configurational preference. Standard quantum chemical methods can predict the favored configurations by using minimum energy calculations on the potential energy landscape. However, the explicit role of the solvent is not revealed by this type of methods. In order to better understand its influence, classical mechanical molecular simulations are applied. It appears from our research that “folding” the ergopeptide molecules into an intermediate state (between the S- and the R-configuration) is mechanically hindered for the preferred configurations.

Computational entropy estimation of linear polyether-modified surfaces and correlation with protein resistant properties of such surfaces

The non-specific adsorption of proteins on surfaces is a well-known and mostly undesirable phenomena, which is reduced by a surface coating with the linear polyether poly(ethylene glycol) (PEG) as the current benchmark material. However, the molecular mechanism of protein-resistant surfaces is still not fully understood. Two main hypotheses are generally applied. The first one is steric repulsion of the highly flexible tethered polymer chains, leading to an entropic penalty by adsorption of proteins due to the reduction in polymer chain mobility. The second one argues with well-hydrated polymer chains generating a repulsive interfacial water layer. In this article, we compare the three different protein-resistant polyether structures PEG, linear polyglycerol (LPG(OH)) and linear poly(methyl glycerol) (LPG(OMe)) to get new insights into the molecular mechanism behind protein resistance. In a theoretical approach, we apply an entropy estimator that assesses the conformational states of the tethered polyethers from MD simulations. It reveals the entropy differences between these polyethers to be in the order PEG>LPG(OH) > LPG(OMe). Moreover, experiments on fibrinogen adsorption of these surfaces via surface plasmon resonance spectroscopy are performed and correlated with the theoretical studies. We find that protein resistant properties of surfaces are likely to arise from an interplay of different factors.

An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells

Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.

Conformational analysis of alternariol on the quantum level

With the help of theoretical calculations we explain the phenomenon of nonplanarity of crystalline alternariol. We find out that the different orientations of the hydroxyl groups of alternariol influence its planarity and aromaticity and lead to different twists of the structure. The presence of the intramolecular hydrogen bond stabilizes the planar geometry while the loss of the bond results in a twist of over 14°. This effect is thought to be involved while cutting DNA strands by alternariol.

Medizin aus dem Computer

ZusammenfassungKleine Moleküle können großen Einfluss auf Stoffwechselprozesse haben. Der computergestützte Wirkstoffentwurf hat zum Ziel, diese kleinen Moleküle derart zu entwickeln, dass sie besonders selektiv und effektiv bestimmte Proteine im Körper adressieren. Im vorliegenden Beitrag wird beschrieben, welche Ideen dem Wirkstoffentwurf zugrunde liegen und wie ein „virtuelles“ Modell für das zu adressierende Protein etabliert wird. Basierend auf diesem Modell kann am Rechner abgeschätzt werden, wie wahrscheinlich vorgegebene Moleküle mit diesem Protein interagieren werden, ohne diese Moleküle dazu chemisch synthetisieren zu müssen. Der moderne, computergestützte Wirkstoffentwurf geht jedoch weit über dieses einfache „Schlüssel-Schloss-Prinzip“ hinaus. Dieser Beitrag informiert daher außerdem über mögliche zukünftige Forschungsfelder und nennt ein erfolgreiches, aktuelles Beispiel des Wirkstoffentwurfs im Bereich der Schmerztherapie.AbstractSmall molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.Small molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.

Medizin aus dem Computer@@@Medicine from the computer

ZusammenfassungKleine Moleküle können großen Einfluss auf Stoffwechselprozesse haben. Der computergestützte Wirkstoffentwurf hat zum Ziel, diese kleinen Moleküle derart zu entwickeln, dass sie besonders selektiv und effektiv bestimmte Proteine im Körper adressieren. Im vorliegenden Beitrag wird beschrieben, welche Ideen dem Wirkstoffentwurf zugrunde liegen und wie ein „virtuelles“ Modell für das zu adressierende Protein etabliert wird. Basierend auf diesem Modell kann am Rechner abgeschätzt werden, wie wahrscheinlich vorgegebene Moleküle mit diesem Protein interagieren werden, ohne diese Moleküle dazu chemisch synthetisieren zu müssen. Der moderne, computergestützte Wirkstoffentwurf geht jedoch weit über dieses einfache „Schlüssel-Schloss-Prinzip“ hinaus. Dieser Beitrag informiert daher außerdem über mögliche zukünftige Forschungsfelder und nennt ein erfolgreiches, aktuelles Beispiel des Wirkstoffentwurfs im Bereich der Schmerztherapie.AbstractSmall molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.Small molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.

Medicine from the computer

ZusammenfassungKleine Moleküle können großen Einfluss auf Stoffwechselprozesse haben. Der computergestützte Wirkstoffentwurf hat zum Ziel, diese kleinen Moleküle derart zu entwickeln, dass sie besonders selektiv und effektiv bestimmte Proteine im Körper adressieren. Im vorliegenden Beitrag wird beschrieben, welche Ideen dem Wirkstoffentwurf zugrunde liegen und wie ein „virtuelles“ Modell für das zu adressierende Protein etabliert wird. Basierend auf diesem Modell kann am Rechner abgeschätzt werden, wie wahrscheinlich vorgegebene Moleküle mit diesem Protein interagieren werden, ohne diese Moleküle dazu chemisch synthetisieren zu müssen. Der moderne, computergestützte Wirkstoffentwurf geht jedoch weit über dieses einfache „Schlüssel-Schloss-Prinzip“ hinaus. Dieser Beitrag informiert daher außerdem über mögliche zukünftige Forschungsfelder und nennt ein erfolgreiches, aktuelles Beispiel des Wirkstoffentwurfs im Bereich der Schmerztherapie.AbstractSmall molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.Small molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.