Standort in Deutschland, wo man günstige und qualitativ hochwertige Kamagra Ohne Rezept Lieferung in jedem Teil der Welt zu kaufen.

Wenn das Problem der Verringerung der Potenz berührt mich persönlich war ich schockiert, dass das passiert gerade mit mir kamagra Übrigens jeder leisten und gibt eine sofortige Wirkung ohne Hausarbeiten Anwendungen.

Microsoft powerpoint - big poster.ppt [read-only]

Two Methods for Identifying PDE Inhibitors
Heidi L. Benson, Y. Vivienne Marsh, James F. Blake, John G. Nygaard and Francis X. Sullivan
Back round of
ground of PDEs
idation Libra
br ry Crea
ary Creation
Conduct HTS to identify inhibitors of PDEx using the following two Phosphodiesterases (PDEs) hydrolyze the second messenger • Goal is to construct a validation library from the array diversity molecules cAMP and cGMP to affect a variety of physiological library that is both representative of each library and diverse for 1.) Virtual HTS of the Validation Library *
processes. Collectively, the literature suggests that discovering Phosphodiesterases (PDEs) regulate the intracellular levels of selective inhibitors of the different PDEs may be therapeutically secondary messengers, cAMP and cGMP, which affects cellular • Homology modeling and database docking method predict which set of •Selections were made on a plate-by-plate basis. For each useful. Recently, several selective PDE inhibitors have been signalling. Eleven families of PDEs have been identified and are compound, the tanimoto similarity was computed via standard 2D developed for various medical indications. Homology modeling classified according to their structure, substrate specificity, tissue • Conduct HTS on highest scoring libraries unity fingerprints to every other compound in the diversity library. and database docking, along with screening subsets of core expression and their responses to inhibitors. Several PDE •For each 96-well plate, the average number of nearest neighbors 2.) Physical HTS of the Validation Library
chemical representatives, are predictive methods for focused inhibitors, such as Viagra (Pfizer), a PDE5 inhibitor for erectile (within 85% similarity) for each compound was computed on an screens. These two methods would drive future drug discovery disfunction, have proven successes in clinical trials and/or are • Test Validation Library is tested hit rates for complete library efforts without requiring the of screening of our entire library already marketed drugs. Other indications for PDE inhibitors •Plates with the highest inter/intra-plate ratio were chosen. This (250,000 compounds). We decided to use IMAP™ technology to include hypertension, congestive heart failure, thrombosis, • Hit rate calculations select, direct and prioritize additional screening ratio of nearest neighbors is designed to rank the most screen for inhibitors against our target PDE to test our theory.
glaucoma, asthma, autoimmune disease and inflammation. IMAP™ is both a homogeneous and non-radioactive assay •Nearly 15,000 compounds were chosen to represent the 250,000 * Array’s Diversity Library (ADL) contains over 250,000 compounds and
technology. This poster reviews our experience with predictive is divided into 70 individual libraries according to their core structures. compounds in Array’s diversity library.
and focused library screens to discover PDE inhibitors. The Validation Library is a sub-selection of the ADL that contains a representative collection of compounds from each library (~15,000 total).
MP to PDE4
Inhibitor I
on Flow Cha
IMAPTM (Immobilized Metal Assay for Phosphochemicals) is a non- •Constructed a homology model of PDEx with Composer, based radioactive, Fluorescence Polarization, homogeneous assay developed by on the published coordinates of PDE4B2B (1.77 Å – PDB Code Molecular Devices. Its proprietary beads are nanoparticles derivatized with trivalent metal ions that bind to a linear form of phosphates or •Coordinates for Array Library compounds were generated via phosphorylated peptides. In the cAMP assay, a low signal is observed when Virtual Screen
the substrate (FL-cAMP) cannot bind to the beads. Conversely, a high FP of Validation
signal occurs when the product (AMP) binds to the beads. •Carried out a virtual screen of the Array Validation library with Validation
GOLD (version 2.0) docking program. Compounds that utilized H-bonds to Gln284 were scored higher. All compounds were (Constructed)
rescored with the Cscore scoring function (Tripos).
Library Screened
•Libraries with the greatest percentage of high scoring compounds Libraries
•Final virtual screen highlighted libraries A-J as sources for potential A recommended reaction assay volume of 20 µL was reduced to 5 µL with minimal signal loss (∆mP of 250 to ~200). Signal was stable for at least 24 hours. HTS IMAP Assay Condit
Screen Statistics
en Statistics
S Results of Vir
Virtual Scr
l Screen-Selected
on Librar
brary Scr
219 Plates Total:
Number of
Number of
# Compounds POC Cutoff # HTS Hits HTS Hit Rate
compounds hits
compounds hits
Virtual Library Picks
Full Library HTS Picks
*PDEx Enzyme-partially purified, expressed in Baculovirus, in-house |---------------- Beckman Coulter FX -----------------|
Beckman Coulter Multimek
Cmpds to 2X
Add 2.5µL
Add 15µL
with PDEx
Results from the HTS show that Libraries B and F had the highest hit & Buffer
rates from the 10 libraries that were chosen from the Virtual Screen. 384 Plate
384 ProxiPlate
384 ProxiPlate
Plate Num ber
HTS Screen Results
HTS Screen Results
Full Library
Library Hit Rate
A. In this PDEx screen, we were able to predict and select focused libraries using the following two methods; Library Picks
Full Library
1.)Virtual screening based on homology modeling and database Validation
2.)Validation Library Screening, which involves screening a representative subset of the diversity library.
B. From the 80,000 compounds selected and screened, each strategy identified the same highest hit libraries, B and F. Validation
C. Within 1 week of completing HTS, confirmed primary hits were resynthesized, their activity confirmed, and initial SAR 14 Libraries were chosen for full library HTS due to their hit rates, interesting structures, and initial SAR observed in the Virtual and the Validation Library screening methods. Libraries “B” and “F” showed the highest hit rates in both the Validation screen set and the full library


2012 Originalarbeiten Schwarzl, M; Huber, S; Maechler, H; Steendijk, P; Seiler, S; Truschnig-Wilders, M; Nestelberger, T; Pieske, BM; Post, H, 2012 Left ventricular diastolic dysfunction during acute myocardial infarction: Effect of mild hypothermia. Resuscitation. 2012; 83(12):1503-1510 Prüller, F; Raggam, RB; Posch, V; Almer, G; Truschnig-Wilders, M; Horejsi, R; Möller, R; Weghuber, D;

Microsoft word - european_guidelines-ak1_doc-end2.doc

Guideline on Actinic Keratoses Developed by the Guideline Subcommittee “Actinic Keratoses” of the European Dermatology Forum Subcommittee Members: Prof. Dr. Eggert Stockfleth, Berlin (Germany) Prof. Dr. Lajos Kemény, Szeged (Hungary) Prof. Dr. Bernt Lindelöf, Stockholm (Sweden) Prof. Dr. Lasse Braathen, Bern (Switzerland) Prof. Dr. Martino Neumann, Rotterdam (Netherlands) P

Copyright © 2010-2014 Internet pdf articles