Pseudoreceptor-based pocket selection in a molecular dynamics simulation of the histamine H4 receptor

There is a renewed interest in pseudoreceptor models which enable computational chemists to bridge the gap of ligand- and receptor-based drug design. We developed a pseudoreceptor model for the histamine H4 receptor (H4R) based on five potent antagonists representing different chemotypes. Here we present the selection of potential ligand binding pockets that occur during molecular dynamics (MD) simulations of a homology-based receptor model. We present a method for prioritizing receptor models according to their match with the consensus ligand-binding mode represented by the pseudoreceptor. In this way, ligand information can be transferred to receptor-based modelling. We use Geometric Hashing to match three-dimensional points in Cartesion space. This allows for the rapid translation- and rotation-free comparison of atom coordinates, which also permits partial matching. The only prerequisite is a hash table, which uses distance triplets as hash keys. Each time a distance triplet occurring in the candidate point set which corresponds to an existing key, the match is represented by a vote of the respective key. Finally, the global match of both point sets can be easily extracted by selection of voted distance triplets. The results revealed a preferred ligand-binding pocket in H4R, which would not have been identified using an unrefined homology model of the protein. The key idea was to rely on ligand information by pseudoreceptor modelling

The Housing Market(s) of San Diego

This paper uses an assignment model to understand the cross section of house prices within a metro area. Movers’ demand for housing is derived from a lifecycle problem with credit market frictions. Equilibrium house prices adjust to assign houses that differ by quality to movers who differ by age, income and wealth. To quantify the model, we measure distributions of house prices, house qualities and mover characteristics from micro data on San Diego County during the 2000s boom. The main result is that cheaper credit for poor households was a major driver of prices, especially at the low end of the market.

Universal Algorithm for Simulating and Evaluating Cyclic Voltammetry at Macroporous Electrodes by Considering Random Arrays of Microelectrodes

An algorithm for the simulation and evaluation of cyclic voltammetry (CV) at macroporous electrodes such as felts, foams, and layered structures is presented. By considering 1D, 2D, and 3D arrays of electrode sheets, cylindrical microelectrodes, hollow‐cylindrical microelectrodes, and hollowspherical microelectrodes the internal diffusion domains of the macroporous structures are approximated. A universal algorithm providing the timedependent surface concentrations of the electrochemically active species, required for simulating cyclic voltammetry responses of the individual planar, cylindrical, and spherical microelectrodes, is presented as well. An essential ingredient of the algorithm, which is based on Laplace integral transformation techniques, is the use of a modified Talbot contour for the inverse Laplace transformation. It is demonstrated that first‐order homogeneous chemical kinetics preceding and/or following the electrochemical reaction and electrochemically active species with non‐equal diffusion coefficients can be included in all diffusion models as well. The proposed theory is supported by experimental data acquired for a reference reaction, the oxidation of [Fe(CN)6]4− at platinum electrodes as well as for a technically relevant reaction, the oxidation of VO2+ at carbon felt electrodes. Based on our calculation strategy, we provide a powerful open source tool for simulating and evaluating CV data implemented into a Python graphical user interface (GUI)

Experimental study of the ageing of building stones exposed to sulfurous and nitric acid atmospheres

During the last few decades, due to remediation procedures, SO2 emissions in the atmosphere have decreased, unlike NOx. Air pollution has changed. Indeed, the aim of this research is to assess the effect of NOx and their interactions with SO2 on stones, particularly on limestones used in Champagne-Ardenne (France) during the restoration processes. Three French building limestones (Courville, Dom and Savonnières) and one reconstituted stone were exposed during 28 days to four strong acid atmospheres i.e. two H2SO3 solutions with different concentrations and two mixed atmospheres with different proportions of HNO3 and H2SO3. These tests produced an intensive acid attack on the stone, allowing the observation of short-term salt precipitation and the evolution of stone properties. Each day, one sample was removed from the acid atmosphere to measure the concentration of SO4(2-) and NO3(-) by ion-chromatography. The surface changes were assessed before and after the tests by 3D scanning and observations with electron microscopy. X-ray microtomography has been performed in the Centre for X-ray Tomography (UGCT) and the Department of Geology at Ghent University (Belgium) in order to observe the penetration of salts and the consequences in stones porosity. First observations showed that exposure to acid atmosphere, led to gypsum efflorescences. Obvious colour changes occurred in all tests. Salt crystallization entailed a change in the porous system, which was evidenced by 3D, mercury porosimetry and X-ray microtomography. Difference between weathered and fresh stone was highlighted by Ion chromatography analyses

Spherical harmonics coeffcients for ligand-based virtual screening of cyclooxygenase inhibitors

Background: Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening. Methodology/Principal Findings: We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization. Conclusions/Significance: 12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort

Can [125I]-Iodocyanopindolol Label β3-Adrenoceptors in Rat Urinary Bladder?

β3-Adrenoceptors have been demonstrated to mediate urinary bladder smooth muscle relaxation but proof of their expression at the protein level has been missing because of lack of suitable antibodies or radioligands. As among various available radioligands [125I]-iodocyanopindolol ([125I]-ICYP) exhibited the smallest problems in labeling cloned human β3-adrenoceptors in previous studies, we have explored its suitability to label β3-adrenoceptors in rat urinary bladder in saturation and competition radioligand binding experiments. Rat lung was used as an internal control and exhibited all characteristics expected from this tissue with regard to β1/β2-adrenoceptor labeling. Saturation and competition binding studies with [125I]-ICYP in rat bladder yielded saturable binding sites with an affinity compatible with β3-adrenoceptors. In competition experiments various agonists and antagonists largely exhibited a profile compatible with a population consisting largely of β3-adrenoceptors. However, the binding competition properties of ICI 118,551 and SR 59,230A were not easily explained by the idea of labeling a homogeneous β3-adrenoceptor population but interpretation of the data was limited by a high degree of non-specific binding in [125I]-ICYP concentrations required to label the receptors. We conclude that [125I]-ICYP can be used to label tissue β3-adrenoceptors but results obtained with this ligand have to be interpreted with caution