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

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

Data collaboration canvas : facilitating data innovation between organizations

The Data Collaboration Canvas (DCC) is a visual framework that allows users to generate ideas for sharing data across (or within) organizations. It can be used by organizations that want to explore the potential of data innovation with other organizations at an early stage of the collaboration to create mutual added value. This simple, visual structuring aid can, among other things, be employed in workshops to identify common potential and hurdles of collaboration. The DCC helps to identify opportunities for data collaboration between companies or within an organization (e.g., between different divisions or departments)

Overcoming Cloud Concerns with Trusted Execution Environments? Exploring the Organizational Perception of a Novel Security Technology in Regulated Swiss Companies

Trusted execution environments are a new approach for isolating data, specific parts of code, or an entire application within untrusted cloud environments. This emerging security technology could also enable the migration to cloud infrastructures for organizations working with highly sensitive data. As current research does not address the organizational perception of trusted execution environments (TEEs), we conducted an explorative study to clarify the technological, environmental, and organizational views on this technology by health care, life sciences, and banking companies in Switzerland. The interview findings show that in these industries, missing technological knowledge as well as privacy and process regulation are perceived to be the most critical driver for organizational adoption of TEEs. The identified low intrinsic motivation to adopt novel technologies permits us to conclude that clarifying the regulatory impact of TEEs could drive future adoption by organizations

THE DATA COLLABORATION CANVAS: A VISUAL FRAMEWORK FOR SYSTEMATICALLY IDENTIFYING AND EVALUATING ORGANIZATIONAL DATA COLLABORATION OPPORTUNITIES

For organizations, the use of Big Data and data analytics provides the opportunity to gain competitive advantages and foster innovation. In most of these data analytics initiatives, it is possible that data from external stakeholders could enrich the internal data assets and lead to enhanced outcomes. Currently, no framework is available that systematically guides practitioners in identifying and evaluating suitable inter-organizational data collaborations at an early stage. This paper closes the gap by following an action design research approach to develop the Data Collaboration Canvas (DCC). The DCC was rigorously evaluated by practitioners from Swiss organizations in six different industries, instantiated in four workshops, and used to guide innovative data collaboration projects. This artifact gives practitioners a guideline for identifying data collaboration opportunities and an insight into the main factors that must be addressed before further pursuing a collaborative partnership

Trusted execution environments : applications and organizational challenges

A lack of trust in the providers is still a major barrier to cloud computing adoption – especially when sensitive data is involved. While current privacy-enhancing technologies, such as homomorphic encryption, can increase security, they come with a considerable performance overhead. As an alternative Trusted Executing Environment (TEE) provides trust guarantees for code execution in the cloud similar to transport layer security for data transport or advanced encryption standard algorithms for data storage. Cloud infrastructure providers like Amazon, Google, and Microsoft introduced TEEs as part of their infrastructure offerings. This review will shed light on the different technological options of TEEs, as well as give insight into organizational issues regarding their usage

Spherical Harmonics Coefficients for Ligand-Based Virtual Screening of Cyclooxygenase Inhibitors

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.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.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

QButterfly : lightweight survey extension for online user interaction studies for non-tech-savvy researchers

We provide a user-friendly, flexible, and lightweight open-source HCI toolkit (github.com/QButterfly) that allows non-tech-savvy researchers to conduct online user interaction studies using the widespread Qualtrics and LimeSurvey platforms. These platforms already provide rich functionality (e.g., for experiments or usability tests) and therefore lend themselves to an extension to display stimulus web pages and record clickstreams. The toolkit consists of a survey template with embedded JavaScript, a JavaScript library embedded in the HTML web pages, and scripts to analyze the collected data. No special programming skills are required to set up a study or match survey data and user interaction data after data collection. We empirically validated the software in a laboratory and a field study. We conclude that this extension, even in its preliminary version, has the potential to make online user interaction studies (e.g., with crowdsourced participants) accessible to a broader range of researchers

Low-melting manganese(II)-based ionic liquids: syntheses, structures, properties and influence of trace impurities

The synthesis of more than 10 new magnetic ionic liquids with [MnX4]2 anions, X = Cl, NCS, NCO, is presented. Detailed structural information through single-crystal X-ray di raction is given for (DMDIm)[Mn(NCS)4], (BnEt3N)2[Mn(NCS)4], and {(Ph3P)2N}2[Mn(NCO4)] 0.6H2O, respectively. All compounds consist of discrete anions and cations with tetrahedrally coordinated Mn(II) atoms. They show paramagnetic behavior as expected for spin-only systems. Melting points are found for several systems below 100 C classifying them as ionic liquids. Thermal properties are investigated using di erential scanning calorimetry (DSC) measurements. The physicochemical properties of density, dynamic viscosity, electrolytic conductivity, and surface tension were measured temperature-dependent of selected samples. These properties are discussed in comparison to similar Co containing systems. An increasing amount of bromide impurity is found to a ect the surface tension only up to 3.3%