Ligand-guided homology modeling drives identification of novel histamine H3 receptor ligands

In this study, we report a ligand-guided homology modeling approach allowing the analysis of relevant binding site residue conformations and the identification of two novel histamine H3 receptor ligands with binding affinity in the nanomolar range. The newly developed method is based on exploiting an essential charge interaction characteristic for aminergic G-protein coupled receptors for ranking 3D receptor models appropriate for the discovery of novel compounds through virtual screening

PyRod Enables Rational Homology Model‐based Virtual Screening Against MCHR1

Several encouraging pre‐clinical results highlight the melanin‐concentrating hormone receptor 1 (MCHR1) as promising target for anti‐obesity drug development. Currently however, experimentally resolved structures of MCHR1 are not available, which complicates rational drug design campaigns. In this study, we aimed at developing accurate, homologymodel‐based 3D pharmacophores against MCHR1. We show that traditional approaches involving docking of known active small molecules are hindered by the flexibility of binding pocket residues. Instead, we derived three‐dimensional pharmacophores from molecular dynamics simulations by employing our novel open‐source software PyRod. In a retrospective evaluation, the generated 3D pharmacophores were highly predictive returning up to 35 % of active molecules and showing an early enrichment (EF1) of up to 27.6. Furthermore, PyRod pharmacophores demonstrate higher sensitivity than ligand‐based pharmacophores and deliver structural insights, which are key to rational lead optimization

Dynamical Casimir Effect in a Designed Leaky Cavity

The phenomenon of particle creation within a resonantly vibrating lossy cavity is investigated for the example of a massless scalar field at finite temperature. Leakage is provided by insertion of a dispersive mirror into a larger ideal cavity. Via the rotating wave approximation we demonstrate that for the case of parametric resonance the exponential growth of the number of created particles and the strong enhancement at finite temperatures are preserved in the presence of reasonable losses. The relevance for experimental tests of quantum radiation via the dynamical Casimir effect is addressed.Comment: 1 figur

Interaction of massive stars with their surroundings

Due to their short lifetimes but their enormous energy release in all stages of their lives massive stars are the major engines for the comic matter circuit. They affect not only their close environment but are also responsible to drive mass flows on galactic scales. Recent 2D models of radiation-driven and wind-blown HII regions are summarized which explore the impact of massive stars to the interstellar medium but find surprisingly small energy transfer efficiencies while an observable Carbon self-enrichment in the Wolf-Rayet phase is detected in the warm ionized gas. Finally, the focus is set on state-of-the-art modelling of HII regions and its present weaknesses with respect to uncertainties and simplifications but on a perspective of the requested art of their modelling in the 21st century.Comment: 7 pages, 3 fig.s, to be published in IAU Symp. No. 252, "The art of modelling stars in the 21st century", L. Deng & K.L. Chang (eds.), 2008, invited tal

Discovery of 9 Ly alpha emitters at redshift z~3.1 using narrow-band imaging and VLT spectroscopy

Narrow-band imaging surveys aimed at detecting the faint emission from the 5007 [O III] line of intracluster planetary nebulae in Virgo also probe high redshift z=3.1 Ly alpha emitters. Here we report on the spectroscopic identification of 9 Ly alpha emitters at z=3.13, obtained with the FORS spectrograph at Unit 1 of the ESO Very Large Telescope (VLT UT1). The spectra of these high redshift objects show a narrow, isolated Ly alpha emission with very faint (frequently undetected) continuum, indicating a large equivalent width. No other features are visible in our spectra. Our Ly alpha emitters are quite similar to those found by Hu (1998), Cowie & Hu (1998) and Hu et al. (1998). Using simple population synthesis models, on the assumption that these sources are regions of star formation, we conclude that the nebulae are nearly optically thick and must have a very low dust content, in order to explain the high observed Ly alpha equivalent widths. For the cosmological and star formation parameters we adopted, the total stellar mass produced would seem to correspond to the formation of rather small galaxies, some of which are perhaps destined to merge. The implied star formation density in our sampled comoving volume is probably somewhat smaller than, but of the same order of magnitude as the star formation density at z=3 derived by other authors from Lyman-break galaxy surveys. This result agrees with the expectation that the Ly alpha emitters are a low-metallicity (or low-dust) tail in a distribution of star forming regions at high redshifts. Finally, the Ly alpha emitters may contribute as many H-ionizing photons as QSOs at z=3.Comment: 26 pages, 17 Postscript figures, ApJ in pres

Next generation 3D pharmacophore modeling

3D pharmacophore models are three‐dimensional ensembles of chemically defined interactions of a ligand in its bioactive conformation. They represent an elegant way to decipher chemically encoded ligand information and have therefore become a valuable tool in drug design. In this review, we provide an overview on the basic concept of this method and summarize key studies for applying 3D pharmacophore models in virtual screening and mechanistic studies for protein functionality. Moreover, we discuss recent developments in the field. The combination of 3D pharmacophore models with molecular dynamics simulations could be a quantum leap forward since these approaches consider macromolecule–ligand interactions as dynamic and therefore show a physiologically relevant interaction pattern. Other trends include the efficient usage of 3D pharmacophore information in machine learning and artificial intelligence applications or freely accessible web servers for 3D pharmacophore modeling. The recent developments show that 3D pharmacophore modeling is a vibrant field with various applications in drug discovery and beyond

Modelling the chemical evolution

Advanced observational facilities allow to trace back the chemical evolution of the Universe, on the one hand, from local objects of different ages and, secondly, by direct observations of redshifted objects. The chemical enrichment serves as one of the cornerstones of cosmological evolution. In order to understand this chemical evolution in morphologically different astrophysical objects models are constructed based on analytical descriptions or numerical methods. For the comparison of their chemical issues, as there are element abundances, gradients, and ratios, with observations not only the present-day values are used but also their temporal evolution from the first era of metal enrichment. Here we will provide some insight into basics of chemical evolution models, highlight advancements, and discuss a few applications.Comment: 12 pages, 3 figures, to appear in the proceedings of "Chemical Abundances in the Universe: Connecting First Stars to Planets". IAU Symposium No. 265, 2009. K. Cunha, M. Spite & B. Barbuy, ed

Dynamical Casimir Effect in a Leaky Cavity at Finite Temperature

The phenomenon of particle creation within an almost resonantly vibrating cavity with losses is investigated for the example of a massless scalar field at finite temperature. A leaky cavity is designed via the insertion of a dispersive mirror into a larger ideal cavity (the reservoir). In the case of parametric resonance the rotating wave approximation allows for the construction of an effective Hamiltonian. The number of produced particles is then calculated using response theory as well as a non-perturbative approach. In addition we study the associated master equation and briefly discuss the effects of detuning. The exponential growth of the particle numbers and the strong enhancement at finite temperatures found earlier for ideal cavities turn out to be essentially preserved. The relevance of the results for experimental tests of quantum radiation via the dynamical Casimir effect is addressed. Furthermore the generalization to the electromagnetic field is outlined.Comment: 48 pages, 8 figures typos corrected & references added and update

Catching a Moving Target: Comparative Modeling of Flaviviral NS2B-NS3 Reveals Small Molecule Zika Protease Inhibitors

The pivotal role of viral proteases in virus replication has already been successfully exploited in several antiviral drug design campaigns. However, no efficient antivirals are currently available against flaviviral infections. In this study, we present lead-like small molecule inhibitors of the Zika Virus (ZIKV) NS2B-NS3 protease. Since only few nonpeptide competitive ligands are known, we take advantage of the high structural similarity with the West Nile Virus (WNV) NS2B-NS3 protease. A comparative modeling approach involving our in-house software PyRod was employed to systematically analyze the binding sites and develop molecular dynamics-based 3D pharmacophores for virtual screening. The identified compounds were biochemically characterized revealing low micromolar affinity for both ZIKV and WNV proteases. Their lead-like properties together with rationalized binding modes represent valuable starting points for future lead optimization. Since the NS2B-NS3 protease is highly conserved among flaviviruses, these compounds may also drive the development of pan-flaviviral antiviral drugs.C.N. thanks the Australian Research Council for a Discovery Early Career Research Award (DE190100015)

Introducing a nationwide registry: the Swiss study on aneurysmal subarachnoid haemorrhage (Swiss SOS)

Background: Aneurysmal subarachnoid haemorrhage (aSAH) is a haemorrhagic form of stroke and occurs in a younger population compared with ischaemic stroke or intracerebral haemorrhage. It accounts for a large proportion of productive life-years lost to stroke. Its surgical and medical treatment represents a multidisciplinary effort. Due to the complexity of the disease, the management remains difficult to standardise and quality of care is accordingly difficult to assess. Objective: To create a registry to assess management parameters of patients treated for aSAH in Switzerland. Methods: A cohort study was initiated with the aim to record characteristics of patients admitted with aSAH, starting January 1st 2009. Ethical committee approval was obtained or is pending from the institutional review boards of all centres. In the study period, seven Swiss hospitals (five university [U], two non-university medical centres) harbouring a neurosurgery department, an intensive care unit and an interventional neuroradiology team so far agreed to participate in the registry (Aarau, Basel [U], Bern [U], Geneva [U], Lausanne [U], St. Gallen, Zürich [U]). Demographic and clinical parameters are entered into a common database. Discussion: This database will soon provide (1) a nationwide assessment of the current standard of care and (2) the outcomes for patients suffering from aSAH in Switzerland. Based on data from this registry, we can conduct cohort comparisons or design diagnostic or therapeutic studies on a national level. Moreover, a standardised registration system will allow healthcare providers to assess the quality of car