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Kalinin S.,Heinrich Heine University Dusseldorf | Peulen T.,Heinrich Heine University Dusseldorf | Sindbert S.,Heinrich Heine University Dusseldorf | Rothwell P.J.,Heinrich Heine University Dusseldorf | And 7 more authors.
Nature Methods | Year: 2012

We present a comprehensive toolkit for Förster resonance energy transfer (FRET)-restrained modeling of biomolecules and their complexes for quantitative applications in structural biology. A dramatic improvement in the precision of FRET-derived structures is achieved by explicitly considering spatial distributions of dye positions, which greatly reduces uncertainties due to flexible dye linkers. The precision and confidence levels of the models are calculated by rigorous error estimation. The accuracy of this approach is demonstrated by docking a DNA primer-template to HIV-1 reverse transcriptase. The derived model agrees with the known X-ray structure with an r.m.s. deviation of 0.5 Å. Furthermore, we introduce FRET-guided 'screening' of a large structural ensemble created by molecular dynamics simulations. We used this hybrid approach to determine the formerly unknown configuration of the flexible single-strand template overhang. © 2012 Nature America, Inc. All rights reserved. Source

Hempel G.,Institute For Pharmazeutische Und Medizinische Chemie | Hempel G.,Universitatsklinikum Munster | Muller H.-J.,Universitatsklinikum Munster | Lanvers-Kaminsky C.,Universitatsklinikum Munster | And 3 more authors.
British Journal of Haematology | Year: 2010

We analysed 1221 serum activity measurements in 168 children from the Berlin-Frankfürt-Münster acute lymphoblastic leukaemia studies, ALL-BFM (Berlin-Frankfürt-Münster) 95 and ALL-BFM REZ, in order to develop a pharmacokinetic model describing the activity-time course of pegylated (PEG)-asparaginase for all dose levels. Patients received 500, 750, 1000 or 2500 U/m2 PEG-asparaginase on up to nine occasions. Serum samples were analysed for asparaginase activity and data analysis was done using nonlinear mixed effects modelling (NONMEM Vers. VI, Globomax, Hanouet, MD, USA). Different linear and nonlinear models were tested. The best model applicable to all dosing groups was a one-compartmental model with clearance (Cl) increasing with time according to the formula: Cl=Cli *e (0·0793 *t) where Cli = initial clearance and t = time after dose. The parameters found were: volume of distribution (V) 1·02 ± 26% l/m2, Cli 59·9 ± 59% ml/d per m2 (mean ± interindividual variability). Interoccasion variability was substantial with 0·183 l/m2 for V and 44·7 ml/d per m2 for Cl, respectively. A subgroup of the patients showed a high clearance, probably due to the development of inactivating antibodies. This is the first model able to predict the activity-time course of PEG-asparaginase at different dosing levels and can therefore be used for developing new dosing regimens. © 2009 Blackwell Publishing Ltd. Source

Hasche A.,Institute For Pharmazeutische Und Medizinische Chemie | Ferenz K.B.,Institute For Pharmazeutische Und Medizinische Chemie | Rose K.,Institute For Pharmazeutische Und Medizinische Chemie | Konig S.,Integrierte Funktionelle Genomik | And 3 more authors.
Neurochemistry International | Year: 2010

Growth factors and their mechanisms of action have been studied extensively. However, it remained widely unrecognized that binding of ATP to growth factors is a prerequisite for their bioactivity. Here we demonstrated the binding of ATP to nerve growth factor (NGF) as well as its relevance for neuroprotection. By using mass spectrometry-based methodology we identified one or two molecules of ATP as being bound to NGF. To test neuroprotective activity of NGF we used primary cultures of rat cortical neurons damaged by staurosporine. ATP was indispensable for the neuroprotective effect of NGF. When the ATP concentration in the culture medium was reduced below approximately 2 nM by adding alkaline phosphatase (AP) or ATPase the neuroprotective activity of NGF was abolished. Site-directed mutagenesis within the heparin-binding domain (HBD) of NGF abolished ATP-binding and the neuroprotective effect. Thus, NGF has to bind ATP to be capable of protecting neurons. © 2009 Elsevier Ltd. Source

Hempel G.,Institute For Pharmazeutische Und Medizinische Chemie | Hempel G.,Universitatsklinikum Munster | Relling M.V.,St Jude Childrens Research Hospital | Stary J.,University Hospital Motol | And 6 more authors.
Pediatric Blood and Cancer | Year: 2010

Background. There is an extreme paucity of pharmacokinetic data for anticancer agents in infants. Therefore, we aimed at characterizing the pharmacokinetics for daunorubicin in infants and examined their relationship to age, body weight, and body surface area. Procedure. Leukemia patients treated according to the Interfant 99 protocol received 30 mg/m2 daunorubicin, with dose reduction to 3/4 for patients 6-12 months old and 2/3 for patients <6 months, respectively. Plasma samples from 21 patients (aged 0.05-1.88 years) were collected and analyzed for daunorubicin and daunorubicinol. Samples from 12 children (age 1.6-18.8 years), who received daunorubicin in an earlier investigation, were used for pharmacokinetic model building using the software NONMEM. Results. Plasma concentration time profiles could be described using a two compartment model. Daunorubicin clearance was 43.9 L hr-1m-2±65% and central volume of distribution 16.4 Lm-2±46%, whereas apparent clearance of daunorubicinol was 19.1 L hr-1m-2±32% and apparent volume of distribution 228 Lm-2±80% (mean± interindividual variability). No age-dependency in any of the BSA-normalized pharmacokinetic parameters was observed. Consequently, due to the empirical dose reduction in infants the overall exposure to daunorubicinol in infants was smaller than would be expected from older children. Patients aged <6 months experienced more infections in the induction phase than the group aged 6-12 months at diagnosis. Other toxicities were similar in both groups. Conclusion. We observed no indication of an age-dependency in the pharmacokinetics of daunorubicin. © 2009 Wiley-Liss, Inc. Source

Yarim M.,Yeditepe University | Koksal M.,Yeditepe University | Schepmann D.,Institute For Pharmazeutische Und Medizinische Chemie | Wunsch B.,Institute For Pharmazeutische Und Medizinische Chemie
Chemical Biology and Drug Design | Year: 2011

To investigate the molecular features involved in sigma (σ) receptors binding, a series of compounds based on indole scaffolds were synthesized and their chemical structures were confirmed by 1H-NMR, IR, and elemental analysis. Their affinity toward σ 1 and σ 2 receptor subtypes was evaluated. 1-{[4-(2-phenylethyl)piperazin-1-yl]methyl}-3-methyl-1H-indole 3b had a high affinity to σ 1 receptors, while three compounds, 1-{3-[4-(substitutedphenyl)piperazin-1-yl]propyl}-1H-indole derivatives 4a-c had shown high affinity and selectivity for σ 2 receptors. Cytotoxicity of the compounds was demonstrated on cancer cell lines from liver (HUH7), breast (MCF7), and colon (HCT-116) cancer cell lines. Compound 1c (3-{[4-(3,4-dichlorobenzyl)piperazin-1-yl]methyl}-1H-indole) showed significant cell growth inhibitory activity on the selected cancer cell lines. © 2011 John Wiley & Sons A/S. Source

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