290 research outputs found
"Meet the e-patient": Chancen und Risiken des Internets für das Verhältnis von Gesundheitsfachleuten und ihren Klienten
No full textPercepção e projeção na prova de Rorschach: Contributos para uma reflexão crítica sobre o modelo de Exner
No full textA partir de uma análise crítica da posição tcórico metodológica de Exner em relação a Prova Projectiva de Rorschach, o autor contesta o reducionismo psicométrico
e restritivamente cognitivista do Sistema
Compreensivo na utilização da referida prova, defendendo a necessidade de se considerar como igualmente
relevantes os factores projectivos e perceptivos na caracterização
dos processos cognitivos subjacentes a
leitura, tratamento c interpretação dos dados Rorschach.Expressing a critical analysis about the Exner’s theoretical and methodological point of vue concerning the Rorschach Test, the author contests the reduction and the restrictivc effects of the psychometric
and the cognitive models on the Comprehensive
System for this test. The author asserts an equal relevance for the projective and perceptive factors of the cognitive process on reading, elaborating and interpreting
Rorschach’s data.A partir d’une analyse critique de la position et theorique et méthodologique de Exner concernant I’Epreuve Projective de Rorschache , l’auteur conteste le réducionisme psychométrique et restrictivement cognitiviste du Système Compréhensif dans I’utilisation
de I’épreuve, soutenant la nécessité de considérer comme pareilleiment pertinents les factcurs et projectifs
et perceptifs dans Ia caractérisation des processus cognitifs sous,jacents a la lecture, traitement et interprétation
des données Rorschach
Nanodiscs for INPHARMA NMR Characterization of GPCRs: Ligand Binding to the Human A2A Adenosine Receptor.
No full textG-protein-coupled-receptors (GPCRs) are of fundamental importance for signal transduction through cell membranes. This makes them important drug targets, but structure-based drug design (SBDD) is still hampered by the limitations for structure determination of unmodified GPCRs. We show that the interligand NOEs for pharmacophore mapping (INPHARMA) method can provide valuable information on ligand poses inside the binding site of the unmodified human A2A adenosine receptor reconstituted in nanodiscs. By comparing experimental INPHARMA spectra with back-calculated spectra based on ligand poses obtained from molecular dynamics simulations, a complex structure for A2A R with the low-affinity ligand 3-pyrrolidin-1-ylquinoxalin-2-amine was determined based on the X-ray structure of ligand ZM-241,358 in complex with a modified A2A R
Scouting novel protein kinase A (PKA) inhibitors by using a consensus docking-based virtual screening approach
No full textpublishe
On-the-Fly Integration of Data from a Spin-Diffusion-Based NMR Experiment into Protein–Ligand Docking
No full textINPHARMA (interligand nuclear Overhauser
enhancement for pharmacophore
mapping) determines the relative orientation of two competitive ligands
in the protein binding pocket. It is based on the observation of interligand
transferred NOEs mediated by spin diffusion through protons of the
protein and is, therefore, sensitive to the specific interactions
of each of the two ligands with the protein. We show how this information
can be directly included into a protein–ligand docking program
to guide the prediction of the complex structures. Agreement between
the experimental and back-calculated spectra based on the full relaxation
matrix approach is translated into a score contribution that is combined
with the scoring function ChemPLP of our docking tool PLANTS. This
combined score is then used to predict the poses of five weakly bound
cAMP-dependent protein kinase (PKA) ligands. After optimizing the
setup, which finally also included trNOE data and optimized protonation
states, very good success rates were obtained for all combinations
of three ligands. For one additional ligand, no conclusive results
could be obtained due to the ambiguous electron density of the ligand
in the X-ray structure, which does not disprove alternative ligand
poses. The failures of the remaining ligand are caused by suboptimal
locations of specific protein side chains. Therefore, side-chain flexibility
should be included in an improved INPHARMA-PLANTS version. This will
reduce the strong dependence on the used protein input structure leading
to improved scores overall, not only for this last ligand
Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53
No full textThe destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery proces
In silico characterisation of AtPARP1 and virtual screening for AtPARP inhibitors to increase resistance to abiotic stress
No full textEs wurde eine virtuelle Screening Route für Arabidopsis thaliana L. PARP (AtPARP) etabliert, um Substanzen zu finden, die zu einer Erhöhung der Trockenstresstoleranz in Pflanzen führen. Die Route basiert auf Homologiemodellen, um effektiv in Datenbanken nach Inhibitoren für pflanzliche PARP zu suchen. Vorgeschlagene Verbindungen wurden in vitro und in planta getestet. ROC und statistische Power Analysis wurden für Docking Studien genutzt, um active von nichtaktiven Strukturen zu unterscheiden. IC50 Werte für 6 Verbindungen waren unter 1 μM. Fünf von 22 Verbindungen zeigten positive Effekte in planta. Aktivitätsdaten wurden genutzt, um ein binäres QSAR Model zu erstellen. Die Substratbindung in AtPARP1 wurde mittels MD Simulationen untersucht. Es wird gezeigt, dass PARP1 in die abiotische Stressantwort involviert ist und effektive Diskriminierung von Inhibitoren und Nichtaktiven unter Verwendung statistischer Methoden möglich ist.A virtual screening route was developed for identification of compounds that lead to an increased drought stress resistance. The route was based on Arabidopsis thaliana L. PARP (AtPARP) homology models to effectively screen databases for plant PARP inhibitors. Proposed compounds were tested on AtPARP1 in vitro and on Lolium perenne plants. ROC and statistical power analysis were applied on docking studies to effectively discriminate potential inhibitors from non-active structures. IC50 values for 6 compounds were below 1 μM. Five of 22 compounds showed a positive effect in planta. Activity data of compounds was used to derive a binary QSAR model. Substrate binding was investigated by comparing MD simulation data with data from other PARP orthologues. The research shows that PARP1 is involved in abiotic stress response in Arabidopsis thaliana and that an effective discrimination of inhibitors from non-actives can be possible, if statistical assumptions are taken into account.vorgelegt von Peter Paul Hey
BINDING, STABILITY, AND NON-BINDING OF MULTI-POLARON SYSTEMS
No full textThe binding of polarons, or its absence, is an old and subtle topic. After defining the model we state some recent theorems of ours. First, the transition from many-body collapse to the existence of a thermodynamic limit for N polarons occurs precisely at U = 2ɑ, where U is the electronic Coulomb repulsion and ɑ is the polaron coupling constant. Second, if U is large enough, there is no multi-polaron binding of any kind. We also discuss the Pekar-Tomasevich approximation to the ground state energy, which is valid for large ɑ. Finally, we derive exact results, not reported before, about the one-dimensional toy model introduced by E. P. Gross
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