Visualizing vascular structures in virtual environments

NASA Astrophysics Data System (ADS)

Wischgoll, Thomas

2013-01-01

In order to learn more about the cause of coronary heart diseases and develop diagnostic tools, the extraction and visualization of vascular structures from volumetric scans for further analysis is an important step. By determining a geometric representation of the vasculature, the geometry can be inspected and additional quantitative data calculated and incorporated into the visualization of the vasculature. To provide a more user-friendly visualization tool, virtual environment paradigms can be utilized. This paper describes techniques for interactive rendering of large-scale vascular structures within virtual environments. This can be applied to almost any virtual environment configuration, such as CAVE-type displays. Specifically, the tools presented in this paper were tested on a Barco I-Space and a large 62x108 inch passive projection screen with a Kinect sensor for user tracking.

Design and Development of ChemInfoCloud: An Integrated Cloud Enabled Platform for Virtual Screening.

PubMed

Karthikeyan, Muthukumarasamy; Pandit, Deepak; Bhavasar, Arvind; Vyas, Renu

2015-01-01

The power of cloud computing and distributed computing has been harnessed to handle vast and heterogeneous data required to be processed in any virtual screening protocol. A cloud computing platorm ChemInfoCloud was built and integrated with several chemoinformatics and bioinformatics tools. The robust engine performs the core chemoinformatics tasks of lead generation, lead optimisation and property prediction in a fast and efficient manner. It has also been provided with some of the bioinformatics functionalities including sequence alignment, active site pose prediction and protein ligand docking. Text mining, NMR chemical shift (1H, 13C) prediction and reaction fingerprint generation modules for efficient lead discovery are also implemented in this platform. We have developed an integrated problem solving cloud environment for virtual screening studies that also provides workflow management, better usability and interaction with end users using container based virtualization, OpenVz.

A Novel Approach for Efficient Pharmacophore-based Virtual Screening: Method and Applications

PubMed Central

Dror, Oranit; Schneidman-Duhovny, Dina; Inbar, Yuval; Nussinov, Ruth; Wolfson, Haim J.

2009-01-01

Virtual screening is emerging as a productive and cost-effective technology in rational drug design for the identification of novel lead compounds. An important model for virtual screening is the pharmacophore. Pharmacophore is the spatial configuration of essential features that enable a ligand molecule to interact with a specific target receptor. In the absence of a known receptor structure, a pharmacophore can be identified from a set of ligands that have been observed to interact with the target receptor. Here, we present a novel computational method for pharmacophore detection and virtual screening. The pharmacophore detection module is able to: (i) align multiple flexible ligands in a deterministic manner without exhaustive enumeration of the conformational space, (ii) detect subsets of input ligands that may bind to different binding sites or have different binding modes, (iii) address cases where the input ligands have different affinities by defining weighted pharmacophores based on the number of ligands that share them, and (iv) automatically select the most appropriate pharmacophore candidates for virtual screening. The algorithm is highly efficient, allowing a fast exploration of the chemical space by virtual screening of huge compound databases. The performance of PharmaGist was successfully evaluated on a commonly used dataset of G-Protein Coupled Receptor alpha1A. Additionally, a large-scale evaluation using the DUD (directory of useful decoys) dataset was performed. DUD contains 2950 active ligands for 40 different receptors, with 36 decoy compounds for each active ligand. PharmaGist enrichment rates are comparable with other state-of-the-art tools for virtual screening. Availability The software is available for download. A user-friendly web interface for pharmacophore detection is available at http://bioinfo3d.cs.tau.ac.il/PharmaGist. PMID:19803502

Promising Aedes aegypti repellent chemotypes identified through integrated QSAE, virtual screening, synthesis, and bioassay

USDA-ARS?s Scientific Manuscript database

Molecular field topology analysis, scaffold hopping, and molecular docking were used as complementary computational tools for the design of repellents for Aedes aegypti, the insect vector for yellow fever, West Nile fever, and dengue fever. A large number of analogues were evaluated by virtual scree...

Tools for building a comprehensive modeling system for virtual screening under real biological conditions: The Computational Titration algorithm.

PubMed

Kellogg, Glen E; Fornabaio, Micaela; Chen, Deliang L; Abraham, Donald J; Spyrakis, Francesca; Cozzini, Pietro; Mozzarelli, Andrea

2006-05-01

Computational tools utilizing a unique empirical modeling system based on the hydrophobic effect and the measurement of logP(o/w) (the partition coefficient for solvent transfer between 1-octanol and water) are described. The associated force field, Hydropathic INTeractions (HINT), contains much rich information about non-covalent interactions in the biological environment because of its basis in an experiment that measures interactions in solution. HINT is shown to be the core of an evolving virtual screening system that is capable of taking into account a number of factors often ignored such as entropy, effects of solvent molecules at the active site, and the ionization states of acidic and basic residues and ligand functional groups. The outline of a comprehensive modeling system for virtual screening that incorporates these features is described. In addition, a detailed description of the Computational Titration algorithm is provided. As an example, three complexes of dihydrofolate reductase (DHFR) are analyzed with our system and these results are compared with the experimental free energies of binding.

Can a virtual reality cognitive training application fulfill a dual role? Using the virtual supermarket cognitive training application as a screening tool for mild cognitive impairment.

PubMed

Zygouris, Stelios; Giakoumis, Dimitrios; Votis, Konstantinos; Doumpoulakis, Stefanos; Ntovas, Konstantinos; Segkouli, Sofia; Karagiannidis, Charalampos; Tzovaras, Dimitrios; Tsolaki, Magda

2015-01-01

Recent research advocates the potential of virtual reality (VR) applications in assessing cognitive functions highlighting the possibility of using a VR application for mild cognitive impairment (MCI) screening. The aim of this study is to investigate whether a VR cognitive training application, the virtual supermarket (VSM), can be used as a screening tool for MCI. Two groups, one of healthy older adults (n = 21) and one of MCI patients (n = 34), were recruited from day centers for cognitive disorders and administered the VSM and a neuropsychological test battery. The performance of the two groups in the VSM was compared and correlated with performance in established neuropsychological tests. At the same time, the effectiveness of a combination of traditional neuropsychological tests and the VSM was examined. VSM displayed a correct classification rate (CCR) of 87.30% when differentiating between MCI patients and healthy older adults, while it was unable to differentiate between MCI subtypes. At the same time, the VSM correlates with various established neuropsychological tests. A limited number of tests were able to improve the CCR of the VSM when combined with the VSM for screening purposes. VSM appears to be a valid method of screening for MCI in an older adult population though it cannot be used for MCI subtype assessment. VSM's concurrent validity is supported by the large number of correlations between the VSM and established tests. It is considered a robust test on its own as the inclusion of other tests failed to improve its CCR significantly.

Exploiting PubChem for Virtual Screening

PubMed Central

Xie, Xiang-Qun

2011-01-01

Importance of the field PubChem is a public molecular information repository, a scientific showcase of the NIH Roadmap Initiative. The PubChem database holds over 27 million records of unique chemical structures of compounds (CID) derived from nearly 70 million substance depositions (SID), and contains more than 449,000 bioassay records with over thousands of in vitro biochemical and cell-based screening bioassays established, with targeting more than 7000 proteins and genes linking to over 1.8 million of substances. Areas covered in this review This review builds on recent PubChem-related computational chemistry research reported by other authors while providing readers with an overview of the PubChem database, focusing on its increasing role in cheminformatics, virtual screening and toxicity prediction modeling. What the reader will gain These publicly available datasets in PubChem provide great opportunities for scientists to perform cheminformatics and virtual screening research for computer-aided drug design. However, the high volume and complexity of the datasets, in particular the bioassay-associated false positives/negatives and highly imbalanced datasets in PubChem, also creates major challenges. Several approaches regarding the modeling of PubChem datasets and development of virtual screening models for bioactivity and toxicity predictions are also reviewed. Take home message Novel data-mining cheminformatics tools and virtual screening algorithms are being developed and used to retrieve, annotate and analyze the large-scale and highly complex PubChem biological screening data for drug design. PMID:21691435

Quantum probability ranking principle for ligand-based virtual screening.

PubMed

Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

2017-04-01

Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.

Quantum probability ranking principle for ligand-based virtual screening

NASA Astrophysics Data System (ADS)

Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

2017-04-01

Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.

A Pipeline To Enhance Ligand Virtual Screening: Integrating Molecular Dynamics and Fingerprints for Ligand and Proteins.

PubMed

Spyrakis, Francesca; Benedetti, Paolo; Decherchi, Sergio; Rocchia, Walter; Cavalli, Andrea; Alcaro, Stefano; Ortuso, Francesco; Baroni, Massimo; Cruciani, Gabriele

2015-10-26

The importance of taking into account protein flexibility in drug design and virtual ligand screening (VS) has been widely debated in the literature, and molecular dynamics (MD) has been recognized as one of the most powerful tools for investigating intrinsic protein dynamics. Nevertheless, deciphering the amount of information hidden in MD simulations and recognizing a significant minimal set of states to be used in virtual screening experiments can be quite complicated. Here we present an integrated MD-FLAP (molecular dynamics-fingerprints for ligand and proteins) approach, comprising a pipeline of molecular dynamics, clustering and linear discriminant analysis, for enhancing accuracy and efficacy in VS campaigns. We first extracted a limited number of representative structures from tens of nanoseconds of MD trajectories by means of the k-medoids clustering algorithm as implemented in the BiKi Life Science Suite ( http://www.bikitech.com [accessed July 21, 2015]). Then, instead of applying arbitrary selection criteria, that is, RMSD, pharmacophore properties, or enrichment performances, we allowed the linear discriminant analysis algorithm implemented in FLAP ( http://www.moldiscovery.com [accessed July 21, 2015]) to automatically choose the best performing conformational states among medoids and X-ray structures. Retrospective virtual screenings confirmed that ensemble receptor protocols outperform single rigid receptor approaches, proved that computationally generated conformations comprise the same quantity/quality of information included in X-ray structures, and pointed to the MD-FLAP approach as a valuable tool for improving VS performances.

Structure-Based Virtual Screening of Commercially Available Compound Libraries.

PubMed

Kireev, Dmitri

2016-01-01

Virtual screening (VS) is an efficient hit-finding tool. Its distinctive strength is that it allows one to screen compound libraries that are not available in the lab. Moreover, structure-based (SB) VS also enables an understanding of how the hit compounds bind the protein target, thus laying ground work for the rational hit-to-lead progression. SBVS requires a very limited experimental effort and is particularly well suited for academic labs and small biotech companies that, unlike pharmaceutical companies, do not have physical access to quality small-molecule libraries. Here, we describe SBVS of commercial compound libraries for Mer kinase inhibitors. The screening protocol relies on the docking algorithm Glide complemented by a post-docking filter based on structural protein-ligand interaction fingerprints (SPLIF).

DOVIS 2.0: an efficient and easy to use parallel virtual screening tool based on AutoDock 4.0.

PubMed

Jiang, Xiaohui; Kumar, Kamal; Hu, Xin; Wallqvist, Anders; Reifman, Jaques

2008-09-08

Small-molecule docking is an important tool in studying receptor-ligand interactions and in identifying potential drug candidates. Previously, we developed a software tool (DOVIS) to perform large-scale virtual screening of small molecules in parallel on Linux clusters, using AutoDock 3.05 as the docking engine. DOVIS enables the seamless screening of millions of compounds on high-performance computing platforms. In this paper, we report significant advances in the software implementation of DOVIS 2.0, including enhanced screening capability, improved file system efficiency, and extended usability. To keep DOVIS up-to-date, we upgraded the software's docking engine to the more accurate AutoDock 4.0 code. We developed a new parallelization scheme to improve runtime efficiency and modified the AutoDock code to reduce excessive file operations during large-scale virtual screening jobs. We also implemented an algorithm to output docked ligands in an industry standard format, sd-file format, which can be easily interfaced with other modeling programs. Finally, we constructed a wrapper-script interface to enable automatic rescoring of docked ligands by arbitrarily selected third-party scoring programs. The significance of the new DOVIS 2.0 software compared with the previous version lies in its improved performance and usability. The new version makes the computation highly efficient by automating load balancing, significantly reducing excessive file operations by more than 95%, providing outputs that conform to industry standard sd-file format, and providing a general wrapper-script interface for rescoring of docked ligands. The new DOVIS 2.0 package is freely available to the public under the GNU General Public License.

μ Opioid receptor: novel antagonists and structural modeling

NASA Astrophysics Data System (ADS)

Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

2016-02-01

The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.

Discovering Novel Alternaria solani Succinate Dehydrogenase Inhibitors by In Silico Modeling and Virtual Screening Strategies to Combat Early Blight

NASA Astrophysics Data System (ADS)

Iftikhar, Sehrish; Shahid, Ahmad A.; Halim, Sobia A.; Wolters, Pieter J.; Vleeshouwers, Vivianne G. A. A.; Khan, Ajmal; Al-Harrasi, Ahmed; Ahmad, Shahbaz

2017-11-01

Alternaria blight is an important foliage disease caused by Alternaria solani. The enzyme Succinate dehydrogenase (SDH) is a potential drug target because of its role in tricarboxylic acid cycle. Hence targeting Alternaria solani SDH enzyme could be efficient tool to design novel fungicides against A. solani. We employed computational methodologies to design new SDH inhibitors using homology modeling; pharmacophore modeling and structure based virtual screening protocol. The three dimensional SDH model showed good stereo-chemical and structural properties. Based on virtual screening results twelve commercially available compounds were purchased and tested in vitro and in vivo. The compounds were found to inhibit mycelial growth of A. solani. Moreover in vitro trials showed that inhibitory effects were enhanced with increase in concentrations. Similarly increased disease control was observed in pre-treated potato tubers. Hence the applied in silico strategy led us to identify new and novel fungicides.

Discovering Novel Alternaria solani Succinate Dehydrogenase Inhibitors by in Silico Modeling and Virtual Screening Strategies to Combat Early Blight

PubMed Central

Iftikhar, Sehrish; Shahid, Ahmad A.; Halim, Sobia A.; Wolters, Pieter J.; Vleeshouwers, Vivianne G. A. A.; Khan, Ajmal; Al-Harrasi, Ahmed; Ahmad, Shahbaz

2017-01-01

Alternaria blight is an important foliage disease caused by Alternaria solani. The enzyme Succinate dehydrogenase (SDH) is a potential drug target because of its role in tricarboxylic acid cycle. Hence targeting Alternaria solani SDH enzyme could be efficient tool to design novel fungicides against A. solani. We employed computational methodologies to design new SDH inhibitors using homology modeling; pharmacophore modeling and structure based virtual screening. The three dimensional SDH model showed good stereo-chemical and structural properties. Based on virtual screening results twelve commercially available compounds were purchased and tested in vitro and in vivo. The compounds were found to inhibit mycelial growth of A. solani. Moreover in vitro trials showed that inhibitory effects were enhanced with increase in concentrations. Similarly increased disease control was observed in pre-treated potato tubers. Hence the applied in silico strategy led us to identify novel fungicides. PMID:29204422

Discovery of Novel HIV-1 Integrase Inhibitors Using QSAR-Based Virtual Screening of the NCI Open Database.

PubMed

Ko, Gene M; Garg, Rajni; Bailey, Barbara A; Kumar, Sunil

2016-01-01

Quantitative structure-activity relationship (QSAR) models can be used as a predictive tool for virtual screening of chemical libraries to identify novel drug candidates. The aims of this paper were to report the results of a study performed for descriptor selection, QSAR model development, and virtual screening for identifying novel HIV-1 integrase inhibitor drug candidates. First, three evolutionary algorithms were compared for descriptor selection: differential evolution-binary particle swarm optimization (DE-BPSO), binary particle swarm optimization, and genetic algorithms. Next, three QSAR models were developed from an ensemble of multiple linear regression, partial least squares, and extremely randomized trees models. A comparison of the performances of three evolutionary algorithms showed that DE-BPSO has a significant improvement over the other two algorithms. QSAR models developed in this study were used in consensus as a predictive tool for virtual screening of the NCI Open Database containing 265,242 compounds to identify potential novel HIV-1 integrase inhibitors. Six compounds were predicted to be highly active (plC50 > 6) by each of the three models. The use of a hybrid evolutionary algorithm (DE-BPSO) for descriptor selection and QSAR model development in drug design is a novel approach. Consensus modeling may provide better predictivity by taking into account a broader range of chemical properties within the data set conducive for inhibition that may be missed by an individual model. The six compounds identified provide novel drug candidate leads in the design of next generation HIV- 1 integrase inhibitors targeting drug resistant mutant viruses.

Low-cost, smartphone based frequency doubling technology visual field testing using virtual reality (Conference Presentation)

NASA Astrophysics Data System (ADS)

Alawa, Karam A.; Sayed, Mohamed; Arboleda, Alejandro; Durkee, Heather A.; Aguilar, Mariela C.; Lee, Richard K.

2017-02-01

Glaucoma is the leading cause of irreversible blindness worldwide. Due to its wide prevalence, effective screening tools are necessary. The purpose of this project is to design and evaluate a system that enables portable, cost effective, smartphone based visual field screening based on frequency doubling technology. The system is comprised of an Android smartphone to display frequency doubling stimuli and handle processing, a Bluetooth remote for user input, and a virtual reality headset to simulate the exam. The LG Nexus 5 smartphone and BoboVR Z3 virtual reality headset were used for their screen size and lens configuration, respectively. The system is capable of running the C-20, N-30, 24-2, and 30-2 testing patterns. Unlike the existing system, the smartphone FDT tests both eyes concurrently by showing the same background to both eyes but only displaying the stimulus to one eye at a time. Both the Humphrey Zeiss FDT and the smartphone FDT were tested on five subjects without a history of ocular disease with the C-20 testing pattern. The smartphone FDT successfully produced frequency doubling stimuli at the correct spatial and temporal frequency. Subjects could not tell which eye was being tested. All five subjects preferred the smartphone FDT to the Humphrey Zeiss FDT due to comfort and ease of use. The smartphone FDT is a low-cost, portable visual field screening device that can be used as a screening tool for glaucoma.

Assessment of wheelchair driving performance in a virtual reality-based simulator

PubMed Central

Mahajan, Harshal P.; Dicianno, Brad E.; Cooper, Rory A.; Ding, Dan

2013-01-01

Objective To develop a virtual reality (VR)-based simulator that can assist clinicians in performing standardized wheelchair driving assessments. Design A completely within-subjects repeated measures design. Methods Participants drove their wheelchairs along a virtual driving circuit modeled after the Power Mobility Road Test (PMRT) and in a hallway with decreasing width. The virtual simulator was displayed on computer screen and VR screens and participants interacted with it using a set of instrumented rollers and a wheelchair joystick. Driving performances of participants were estimated and compared using quantitative metrics from the simulator. Qualitative ratings from two experienced clinicians were used to estimate intra- and inter-rater reliability. Results Ten regular wheelchair users (seven men, three women; mean age ± SD, 39.5 ± 15.39 years) participated. The virtual PMRT scores from the two clinicians show high inter-rater reliability (78–90%) and high intra-rater reliability (71–90%) for all test conditions. More research is required to explore user preferences and effectiveness of the two control methods (rollers and mathematical model) and the display screens. Conclusions The virtual driving simulator seems to be a promising tool for wheelchair driving assessment that clinicians can use to supplement their real-world evaluations. PMID:23820148

Rocker: Open source, easy-to-use tool for AUC and enrichment calculations and ROC visualization.

PubMed

Lätti, Sakari; Niinivehmas, Sanna; Pentikäinen, Olli T

2016-01-01

Receiver operating characteristics (ROC) curve with the calculation of area under curve (AUC) is a useful tool to evaluate the performance of biomedical and chemoinformatics data. For example, in virtual drug screening ROC curves are very often used to visualize the efficiency of the used application to separate active ligands from inactive molecules. Unfortunately, most of the available tools for ROC analysis are implemented into commercially available software packages, or are plugins in statistical software, which are not always the easiest to use. Here, we present Rocker, a simple ROC curve visualization tool that can be used for the generation of publication quality images. Rocker also includes an automatic calculation of the AUC for the ROC curve and Boltzmann-enhanced discrimination of ROC (BEDROC). Furthermore, in virtual screening campaigns it is often important to understand the early enrichment of active ligand identification, for this Rocker offers automated calculation routine. To enable further development of Rocker, it is freely available (MIT-GPL license) for use and modifications from our web-site (http://www.jyu.fi/rocker).

MegaMiner: A Tool for Lead Identification Through Text Mining Using Chemoinformatics Tools and Cloud Computing Environment.

PubMed

Karthikeyan, Muthukumarasamy; Pandit, Yogesh; Pandit, Deepak; Vyas, Renu

2015-01-01

Virtual screening is an indispensable tool to cope with the massive amount of data being tossed by the high throughput omics technologies. With the objective of enhancing the automation capability of virtual screening process a robust portal termed MegaMiner has been built using the cloud computing platform wherein the user submits a text query and directly accesses the proposed lead molecules along with their drug-like, lead-like and docking scores. Textual chemical structural data representation is fraught with ambiguity in the absence of a global identifier. We have used a combination of statistical models, chemical dictionary and regular expression for building a disease specific dictionary. To demonstrate the effectiveness of this approach, a case study on malaria has been carried out in the present work. MegaMiner offered superior results compared to other text mining search engines, as established by F score analysis. A single query term 'malaria' in the portlet led to retrieval of related PubMed records, protein classes, drug classes and 8000 scaffolds which were internally processed and filtered to suggest new molecules as potential anti-malarials. The results obtained were validated by docking the virtual molecules into relevant protein targets. It is hoped that MegaMiner will serve as an indispensable tool for not only identifying hidden relationships between various biological and chemical entities but also for building better corpus and ontologies.

Role of Chemical Reactivity and Transition State Modeling for Virtual Screening.

PubMed

Karthikeyan, Muthukumarasamy; Vyas, Renu; Tambe, Sanjeev S; Radhamohan, Deepthi; Kulkarni, Bhaskar D

2015-01-01

Every drug discovery research program involves synthesis of a novel and potential drug molecule utilizing atom efficient, economical and environment friendly synthetic strategies. The current work focuses on the role of the reactivity based fingerprints of compounds as filters for virtual screening using a tool ChemScore. A reactant-like (RLS) and a product- like (PLS) score can be predicted for a given compound using the binary fingerprints derived from the numerous known organic reactions which capture the molecule-molecule interactions in the form of addition, substitution, rearrangement, elimination and isomerization reactions. The reaction fingerprints were applied to large databases in biology and chemistry, namely ChEMBL, KEGG, HMDB, DSSTox, and the Drug Bank database. A large network of 1113 synthetic reactions was constructed to visualize and ascertain the reactant product mappings in the chemical reaction space. The cumulative reaction fingerprints were computed for 4000 molecules belonging to 29 therapeutic classes of compounds, and these were found capable of discriminating between the cognition disorder related and anti-allergy compounds with reasonable accuracy of 75% and AUC 0.8. In this study, the transition state based fingerprints were also developed and used effectively for virtual screening in drug related databases. The methodology presented here provides an efficient handle for the rapid scoring of molecular libraries for virtual screening.

Applying DEKOIS 2.0 in structure-based virtual screening to probe the impact of preparation procedures and score normalization.

PubMed

Ibrahim, Tamer M; Bauer, Matthias R; Boeckler, Frank M

2015-01-01

Structure-based virtual screening techniques can help to identify new lead structures and complement other screening approaches in drug discovery. Prior to docking, the data (protein crystal structures and ligands) should be prepared with great attention to molecular and chemical details. Using a subset of 18 diverse targets from the recently introduced DEKOIS 2.0 benchmark set library, we found differences in the virtual screening performance of two popular docking tools (GOLD and Glide) when employing two different commercial packages (e.g. MOE and Maestro) for preparing input data. We systematically investigated the possible factors that can be responsible for the found differences in selected sets. For the Angiotensin-I-converting enzyme dataset, preparation of the bioactive molecules clearly exerted the highest influence on VS performance compared to preparation of the decoys or the target structure. The major contributing factors were different protonation states, molecular flexibility, and differences in the input conformation (particularly for cyclic moieties) of bioactives. In addition, score normalization strategies eliminated the biased docking scores shown by GOLD (ChemPLP) for the larger bioactives and produced a better performance. Generalizing these normalization strategies on the 18 DEKOIS 2.0 sets, improved the performances for the majority of GOLD (ChemPLP) docking, while it showed detrimental performances for the majority of Glide (SP) docking. In conclusion, we exemplify herein possible issues particularly during the preparation stage of molecular data and demonstrate to which extent these issues can cause perturbations in the virtual screening performance. We provide insights into what problems can occur and should be avoided, when generating benchmarks to characterize the virtual screening performance. Particularly, careful selection of an appropriate molecular preparation setup for the bioactive set and the use of score normalization for docking with GOLD (ChemPLP) appear to have a great importance for the screening performance. For virtual screening campaigns, we recommend to invest time and effort into including alternative preparation workflows into the generation of the master library, even at the cost of including multiple representations of each molecule. Graphical AbstractUsing DEKOIS 2.0 benchmark sets in structure-based virtual screening to probe the impact of molecular preparation and score normalization.

Approaches to virtual screening and screening library selection.

PubMed

Wildman, Scott A

2013-01-01

The ease of access to virtual screening (VS) software in recent years has resulted in a large increase in literature reports. Over 300 publications in the last year report the use of virtual screening techniques to identify new chemical matter or present the development of new virtual screening techniques. The increased use is accompanied by a corresponding increase in misuse and misinterpretation of virtual screening results. This review aims to identify many of the common difficulties associated with virtual screening and allow researchers to better assess the reliability of their virtual screening effort.

JADOPPT: java based AutoDock preparing and processing tool.

PubMed

García-Pérez, Carlos; Peláez, Rafael; Therón, Roberto; Luis López-Pérez, José

2017-02-15

AutoDock is a very popular software package for docking and virtual screening. However, currently it is hard work to visualize more than one result from the virtual screening at a time. To overcome this limitation we have designed JADOPPT, a tool for automatically preparing and processing multiple ligand-protein docked poses obtained from AutoDock. It allows the simultaneous visual assessment and comparison of multiple poses through clustering methods. Moreover, it permits the representation of reference ligands with known binding modes, binding site residues, highly scoring regions for the ligand, and the calculated binding energy of the best ranked results. JADOPPT, supplementary material (Case Studies 1 and 2) and video tutorials are available at http://visualanalytics.land/cgarcia/JADOPPT.html. carlosgarcia@usal.es or pelaez@usal.es. Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Design of efficient molecular organic light-emitting diodes by a high-throughput virtual screening and experimental approach.

PubMed

Gómez-Bombarelli, Rafael; Aguilera-Iparraguirre, Jorge; Hirzel, Timothy D; Duvenaud, David; Maclaurin, Dougal; Blood-Forsythe, Martin A; Chae, Hyun Sik; Einzinger, Markus; Ha, Dong-Gwang; Wu, Tony; Markopoulos, Georgios; Jeon, Soonok; Kang, Hosuk; Miyazaki, Hiroshi; Numata, Masaki; Kim, Sunghan; Huang, Wenliang; Hong, Seong Ik; Baldo, Marc; Adams, Ryan P; Aspuru-Guzik, Alán

2016-10-01

Virtual screening is becoming a ground-breaking tool for molecular discovery due to the exponential growth of available computer time and constant improvement of simulation and machine learning techniques. We report an integrated organic functional material design process that incorporates theoretical insight, quantum chemistry, cheminformatics, machine learning, industrial expertise, organic synthesis, molecular characterization, device fabrication and optoelectronic testing. After exploring a search space of 1.6 million molecules and screening over 400,000 of them using time-dependent density functional theory, we identified thousands of promising novel organic light-emitting diode molecules across the visible spectrum. Our team collaboratively selected the best candidates from this set. The experimentally determined external quantum efficiencies for these synthesized candidates were as large as 22%.

Design of efficient molecular organic light-emitting diodes by a high-throughput virtual screening and experimental approach

NASA Astrophysics Data System (ADS)

Gómez-Bombarelli, Rafael; Aguilera-Iparraguirre, Jorge; Hirzel, Timothy D.; Duvenaud, David; MacLaurin, Dougal; Blood-Forsythe, Martin A.; Chae, Hyun Sik; Einzinger, Markus; Ha, Dong-Gwang; Wu, Tony; Markopoulos, Georgios; Jeon, Soonok; Kang, Hosuk; Miyazaki, Hiroshi; Numata, Masaki; Kim, Sunghan; Huang, Wenliang; Hong, Seong Ik; Baldo, Marc; Adams, Ryan P.; Aspuru-Guzik, Alán

2016-10-01

Virtual screening is becoming a ground-breaking tool for molecular discovery due to the exponential growth of available computer time and constant improvement of simulation and machine learning techniques. We report an integrated organic functional material design process that incorporates theoretical insight, quantum chemistry, cheminformatics, machine learning, industrial expertise, organic synthesis, molecular characterization, device fabrication and optoelectronic testing. After exploring a search space of 1.6 million molecules and screening over 400,000 of them using time-dependent density functional theory, we identified thousands of promising novel organic light-emitting diode molecules across the visible spectrum. Our team collaboratively selected the best candidates from this set. The experimentally determined external quantum efficiencies for these synthesized candidates were as large as 22%.

Using Virtual Patient Simulations to Prepare Primary Health Care Professionals to Conduct Substance Use and Mental Health Screening and Brief Intervention.

PubMed

Albright, Glenn; Bryan, Craig; Adam, Cyrille; McMillan, Jeremiah; Shockley, Kristen

Primary health care professionals are in an excellent position to identify, screen, and conduct brief interventions for patients with mental health and substance use disorders. However, discomfort in initiating conversations about behavioral health, time concerns, lack of knowledge about screening tools, and treatment resources are barriers. This study examines the impact of an online simulation where users practice role-playing with emotionally responsive virtual patients to learn motivational interviewing strategies to better manage screening, brief interventions, and referral conversations. Baseline data were collected from 227 participants who were then randomly assigned into the treatment or wait-list control groups. Treatment group participants then completed the simulation, postsimulation survey, and 3-month follow-up survey. Results showed significant increases in knowledge/skill to identify and engage in collaborative decision making with patients. Results strongly suggest that role-play simulation experiences can be an effective means of teaching screening and brief intervention.

DOVIS: an implementation for high-throughput virtual screening using AutoDock.

PubMed

Zhang, Shuxing; Kumar, Kamal; Jiang, Xiaohui; Wallqvist, Anders; Reifman, Jaques

2008-02-27

Molecular-docking-based virtual screening is an important tool in drug discovery that is used to significantly reduce the number of possible chemical compounds to be investigated. In addition to the selection of a sound docking strategy with appropriate scoring functions, another technical challenge is to in silico screen millions of compounds in a reasonable time. To meet this challenge, it is necessary to use high performance computing (HPC) platforms and techniques. However, the development of an integrated HPC system that makes efficient use of its elements is not trivial. We have developed an application termed DOVIS that uses AutoDock (version 3) as the docking engine and runs in parallel on a Linux cluster. DOVIS can efficiently dock large numbers (millions) of small molecules (ligands) to a receptor, screening 500 to 1,000 compounds per processor per day. Furthermore, in DOVIS, the docking session is fully integrated and automated in that the inputs are specified via a graphical user interface, the calculations are fully integrated with a Linux cluster queuing system for parallel processing, and the results can be visualized and queried. DOVIS removes most of the complexities and organizational problems associated with large-scale high-throughput virtual screening, and provides a convenient and efficient solution for AutoDock users to use this software in a Linux cluster platform.

Making Conjectures in Dynamic Geometry: The Potential of a Particular Way of Dragging

ERIC Educational Resources Information Center

Mariotti, Maria Alessandra; Baccaglini-Frank, Anna

2011-01-01

When analyzing what has changed in the geometry scenario with the advent of dynamic geometry systems (DGS), one can notice a transition from the traditional graphic environment made of paper-and-pencil, and the classical construction tools like the ruler and compass, to a virtual graphic space, made of a computer screen, graphical tools that are…

Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays

PubMed Central

Shen, Mingyun; Tian, Sheng; Pan, Peichen; Sun, Huiyong; Li, Dan; Li, Youyong; Zhou, Hefeng; Li, Chuwen; Lee, Simon Ming-Yuen; Hou, Tingjun

2015-01-01

Rho-associated kinases (ROCKs) have been regarded as promising drug targets for the treatment of cardiovascular diseases, nervous system diseases and cancers. In this study, a novel integrated virtual screening protocol by combining molecular docking and pharmacophore mapping based on multiple ROCK1 crystal structures was utilized to screen the ChemBridge database for discovering potential inhibitors of ROCK1. Among the 38 tested compounds, seven of them exhibited significant inhibitory activities of ROCK1 (IC50 < 10 μM) and the most potent one (compound TS-f22) with the novel scaffold of 4-Phenyl-1H-pyrrolo [2,3-b] pyridine had an IC50 of 480 nM. Then, the structure-activity relationships of 41 analogues of TS-f22 were examined. Two potent inhibitors were proven effective in inhibiting the phosphorylation of the downstream target in the ROCK signaling pathway in vitro and protecting atorvastatin-induced cerebral hemorrhage in vivo. The high hit rate (28.95%) suggested that the integrated virtual screening strategy was quite reliable and could be used as a powerful tool for identifying promising active compounds for targets of interest. PMID:26568382

Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays.

PubMed

Shen, Mingyun; Tian, Sheng; Pan, Peichen; Sun, Huiyong; Li, Dan; Li, Youyong; Zhou, Hefeng; Li, Chuwen; Lee, Simon Ming-Yuen; Hou, Tingjun

2015-11-16

Rho-associated kinases (ROCKs) have been regarded as promising drug targets for the treatment of cardiovascular diseases, nervous system diseases and cancers. In this study, a novel integrated virtual screening protocol by combining molecular docking and pharmacophore mapping based on multiple ROCK1 crystal structures was utilized to screen the ChemBridge database for discovering potential inhibitors of ROCK1. Among the 38 tested compounds, seven of them exhibited significant inhibitory activities of ROCK1 (IC50 < 10 μM) and the most potent one (compound TS-f22) with the novel scaffold of 4-Phenyl-1H-pyrrolo [2,3-b] pyridine had an IC50 of 480 nM. Then, the structure-activity relationships of 41 analogues of TS-f22 were examined. Two potent inhibitors were proven effective in inhibiting the phosphorylation of the downstream target in the ROCK signaling pathway in vitro and protecting atorvastatin-induced cerebral hemorrhage in vivo. The high hit rate (28.95%) suggested that the integrated virtual screening strategy was quite reliable and could be used as a powerful tool for identifying promising active compounds for targets of interest.

VSDMIP: virtual screening data management on an integrated platform

NASA Astrophysics Data System (ADS)

Gil-Redondo, Rubén; Estrada, Jorge; Morreale, Antonio; Herranz, Fernando; Sancho, Javier; Ortiz, Ángel R.

2009-03-01

A novel software (VSDMIP) for the virtual screening (VS) of chemical libraries integrated within a MySQL relational database is presented. Two main features make VSDMIP clearly distinguishable from other existing computational tools: (i) its database, which stores not only ligand information but also the results from every step in the VS process, and (ii) its modular and pluggable architecture, which allows customization of the VS stages (such as the programs used for conformer generation or docking), through the definition of a detailed workflow employing user-configurable XML files. VSDMIP, therefore, facilitates the storage and retrieval of VS results, easily adapts to the specific requirements of each method and tool used in the experiments, and allows the comparison of different VS methodologies. To validate the usefulness of VSDMIP as an automated tool for carrying out VS several experiments were run on six protein targets (acetylcholinesterase, cyclin-dependent kinase 2, coagulation factor Xa, estrogen receptor alpha, p38 MAP kinase, and neuraminidase) using nine binary (actives/inactive) test sets. The performance of several VS configurations was evaluated by means of enrichment factors and receiver operating characteristic plots.

MLViS: A Web Tool for Machine Learning-Based Virtual Screening in Early-Phase of Drug Discovery and Development

PubMed Central

Korkmaz, Selcuk; Zararsiz, Gokmen; Goksuluk, Dincer

2015-01-01

Virtual screening is an important step in early-phase of drug discovery process. Since there are thousands of compounds, this step should be both fast and effective in order to distinguish drug-like and nondrug-like molecules. Statistical machine learning methods are widely used in drug discovery studies for classification purpose. Here, we aim to develop a new tool, which can classify molecules as drug-like and nondrug-like based on various machine learning methods, including discriminant, tree-based, kernel-based, ensemble and other algorithms. To construct this tool, first, performances of twenty-three different machine learning algorithms are compared by ten different measures, then, ten best performing algorithms have been selected based on principal component and hierarchical cluster analysis results. Besides classification, this application has also ability to create heat map and dendrogram for visual inspection of the molecules through hierarchical cluster analysis. Moreover, users can connect the PubChem database to download molecular information and to create two-dimensional structures of compounds. This application is freely available through www.biosoft.hacettepe.edu.tr/MLViS/. PMID:25928885

Virtual Screening and X-ray Crystallography for Human Kallikrein 6 Inhibitors with an Amidinothiophene P1 Group.

PubMed

Liang, Guyan; Chen, Xin; Aldous, Suzanne; Pu, Su-Fen; Mehdi, Shujaath; Powers, Elaine; Giovanni, Andrew; Kongsamut, Sathapana; Xia, Tianhui; Zhang, Ying; Wang, Rachel; Gao, Zhongli; Merriman, Gregory; McLean, Larry R; Morize, Isabelle

2012-02-09

A series of compounds with an amidinothiophene P1 group and a pyrrolidinone-sulphonamide scaffold linker was identified as potent inhibitors of human kallikrein 6 by structure-based virtual screening based on the union accessible binding space of serine proteases. As the first series of potent nonmechanism-based hK6 inhibitors, they may be used as tool compounds for target validation. An X-ray structure of a representative compound complexed with hK6, resolved at a resolution of 1.88 Å, revealed that the amidinothiophene moiety bound in the S1 pocket and the pyrrolidinone-sulphonamide linker projected the aromatic tail into the S' pocket.

Identifying Novel Type ZBGs and Nonhydroxamate HDAC Inhibitors Through a SVM Based Virtual Screening Approach.

PubMed

Liu, X H; Song, H Y; Zhang, J X; Han, B C; Wei, X N; Ma, X H; Cui, W K; Chen, Y Z

2010-05-17

Histone deacetylase inhibitors (HDACi) have been successfully used for the treatment of cancers and other diseases. Search for novel type ZBGs and development of non-hydroxamate HDACi has become a focus in current research. To complement this, it is desirable to explore a virtual screening (VS) tool capable of identifying different types of potential inhibitors from large compound libraries with high yields and low false-hit rates similar to HTS. This work explored the use of support vector machines (SVM) combined with our newly developed putative non-inhibitor generation method as such a tool. SVM trained by 702 pre-2008 hydroxamate HDACi and 64334 putative non-HDACi showed good yields and low false-hit rates in cross-validation test and independent test using 220 diverse types of HDACi reported since 2008. The SVM hit rates in scanning 13.56 M PubChem and 168K MDDR compounds are comparable to HTS rates. Further structural analysis of SVM virtual hits suggests its potential for identification of non-hydroxamate HDACi. From this analysis, a series of novel ZBG and cap groups were proposed for HDACi design. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan

NASA Astrophysics Data System (ADS)

Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

2011-06-01

The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan.

PubMed

Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

2011-06-01

The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

Pharmacophore Models and Pharmacophore-Based Virtual Screening: Concepts and Applications Exemplified on Hydroxysteroid Dehydrogenases.

PubMed

Kaserer, Teresa; Beck, Katharina R; Akram, Muhammad; Odermatt, Alex; Schuster, Daniela

2015-12-19

Computational methods are well-established tools in the drug discovery process and can be employed for a variety of tasks. Common applications include lead identification and scaffold hopping, as well as lead optimization by structure-activity relationship analysis and selectivity profiling. In addition, compound-target interactions associated with potentially harmful effects can be identified and investigated. This review focuses on pharmacophore-based virtual screening campaigns specifically addressing the target class of hydroxysteroid dehydrogenases. Many members of this enzyme family are associated with specific pathological conditions, and pharmacological modulation of their activity may represent promising therapeutic strategies. On the other hand, unintended interference with their biological functions, e.g., upon inhibition by xenobiotics, can disrupt steroid hormone-mediated effects, thereby contributing to the development and progression of major diseases. Besides a general introduction to pharmacophore modeling and pharmacophore-based virtual screening, exemplary case studies from the field of short-chain dehydrogenase/reductase (SDR) research are presented. These success stories highlight the suitability of pharmacophore modeling for the various application fields and suggest its application also in futures studies.

[Virtual microscopy in pathology teaching and postgraduate training (continuing education)].

PubMed

Sinn, H P; Andrulis, M; Mogler, C; Schirmacher, P

2008-11-01

As with conventional microscopy, virtual microscopy permits histological tissue sections to be viewed on a computer screen with a free choice of viewing areas and a wide range of magnifications. This, combined with the possibility of linking virtual microscopy to E-Learning courses, make virtual microscopy an ideal tool for teaching and postgraduate training in pathology. Uses of virtual microscopy in pathology teaching include blended learning with the presentation of digital teaching slides in the internet parallel to presentation in the histology lab, extending student access to histology slides beyond the lab. Other uses are student self-learning in the Internet, as well as the presentation of virtual slides in the classroom with or without replacing real microscopes. Successful integration of virtual microscopy depends on its embedding in the virtual classroom and the creation of interactive E-learning content. Applications derived from this include the use of virtual microscopy in video clips, podcasts, SCORM modules and the presentation of virtual microscopy using interactive whiteboards in the classroom.

A web-based platform for virtual screening.

PubMed

Watson, Paul; Verdonk, Marcel; Hartshorn, Michael J

2003-09-01

A fully integrated, web-based, virtual screening platform has been developed to allow rapid virtual screening of large numbers of compounds. ORACLE is used to store information at all stages of the process. The system includes a large database of historical compounds from high throughput screenings (HTS) chemical suppliers, ATLAS, containing over 3.1 million unique compounds with their associated physiochemical properties (ClogP, MW, etc.). The database can be screened using a web-based interface to produce compound subsets for virtual screening or virtual library (VL) enumeration. In order to carry out the latter task within ORACLE a reaction data cartridge has been developed. Virtual libraries can be enumerated rapidly using the web-based interface to the cartridge. The compound subsets can be seamlessly submitted for virtual screening experiments, and the results can be viewed via another web-based interface allowing ad hoc querying of the virtual screening data stored in ORACLE.

Hierarchical virtual screening approaches in small molecule drug discovery.

PubMed

Kumar, Ashutosh; Zhang, Kam Y J

2015-01-01

Virtual screening has played a significant role in the discovery of small molecule inhibitors of therapeutic targets in last two decades. Various ligand and structure-based virtual screening approaches are employed to identify small molecule ligands for proteins of interest. These approaches are often combined in either hierarchical or parallel manner to take advantage of the strength and avoid the limitations associated with individual methods. Hierarchical combination of ligand and structure-based virtual screening approaches has received noteworthy success in numerous drug discovery campaigns. In hierarchical virtual screening, several filters using ligand and structure-based approaches are sequentially applied to reduce a large screening library to a number small enough for experimental testing. In this review, we focus on different hierarchical virtual screening strategies and their application in the discovery of small molecule modulators of important drug targets. Several virtual screening studies are discussed to demonstrate the successful application of hierarchical virtual screening in small molecule drug discovery. Copyright © 2014 Elsevier Inc. All rights reserved.

DOCKTITE-a highly versatile step-by-step workflow for covalent docking and virtual screening in the molecular operating environment.

PubMed

Scholz, Christoph; Knorr, Sabine; Hamacher, Kay; Schmidt, Boris

2015-02-23

The formation of a covalent bond with the target is essential for a number of successful drugs, yet tools for covalent docking without significant restrictions regarding warhead or receptor classes are rare and limited in use. In this work we present DOCKTITE, a highly versatile workflow for covalent docking in the Molecular Operating Environment (MOE) combining automated warhead screening, nucleophilic side chain attachment, pharmacophore-based docking, and a novel consensus scoring approach. The comprehensive validation study includes pose predictions of 35 protein/ligand complexes which resulted in a mean RMSD of 1.74 Å and a prediction rate of 71.4% with an RMSD below 2 Å, a virtual screening with an area under the curve (AUC) for the receiver operating characteristics (ROC) of 0.81, and a significant correlation between predicted and experimental binding affinities (ρ = 0.806, R(2) = 0.649, p < 0.005).

PhAST: pharmacophore alignment search tool.

PubMed

Hähnke, Volker; Hofmann, Bettina; Grgat, Tomislav; Proschak, Ewgenij; Steinhilber, Dieter; Schneider, Gisbert

2009-04-15

We present a ligand-based virtual screening technique (PhAST) for rapid hit and lead structure searching in large compound databases. Molecules are represented as strings encoding the distribution of pharmacophoric features on the molecular graph. In contrast to other text-based methods using SMILES strings, we introduce a new form of text representation that describes the pharmacophore of molecules. This string representation opens the opportunity for revealing functional similarity between molecules by sequence alignment techniques in analogy to homology searching in protein or nucleic acid sequence databases. We favorably compared PhAST with other current ligand-based virtual screening methods in a retrospective analysis using the BEDROC metric. In a prospective application, PhAST identified two novel inhibitors of 5-lipoxygenase product formation with minimal experimental effort. This outcome demonstrates the applicability of PhAST to drug discovery projects and provides an innovative concept of sequence-based compound screening with substantial scaffold hopping potential. 2008 Wiley Periodicals, Inc.

SPOT-ligand 2: improving structure-based virtual screening by binding-homology search on an expanded structural template library.

PubMed

Litfin, Thomas; Zhou, Yaoqi; Yang, Yuedong

2017-04-15

The high cost of drug discovery motivates the development of accurate virtual screening tools. Binding-homology, which takes advantage of known protein-ligand binding pairs, has emerged as a powerful discrimination technique. In order to exploit all available binding data, modelled structures of ligand-binding sequences may be used to create an expanded structural binding template library. SPOT-Ligand 2 has demonstrated significantly improved screening performance over its previous version by expanding the template library 15 times over the previous one. It also performed better than or similar to other binding-homology approaches on the DUD and DUD-E benchmarks. The server is available online at http://sparks-lab.org . yaoqi.zhou@griffith.edu.au or yuedong.yang@griffith.edu.au. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Human recombinant beta-secretase immobilized enzyme reactor for fast hits' selection and characterization from a virtual screening library.

PubMed

De Simone, Angela; Mancini, Francesca; Cosconati, Sandro; Marinelli, Luciana; La Pietra, Valeria; Novellino, Ettore; Andrisano, Vincenza

2013-01-25

In the present work, a human recombinant BACE1 immobilized enzyme reactor (hrBACE1-IMER) has been applied for the sensitive fast screening of 38 compounds selected through a virtual screening approach. HrBACE1-IMER was inserted into a liquid chromatograph coupled with a fluorescent detector. A fluorogenic peptide substrate (M-2420), containing the β-secretase site of the Swedish mutation of APP, was injected and cleaved in the on-line HPLC-hrBACE1-IMER system, giving rise to the fluorescent product. The compounds of the library were tested for their ability to inhibit BACE1 in the immobilized format and to reduce the area related to the chromatographic peak of the fluorescent enzymatic product. The results were validated in solution by using two different FRET methods. Due to the efficient virtual screening methodology, more than fifty percent of the selected compounds showed a measurable inhibitory activity. One of the most active compound (a bis-indanone derivative) was characterized in terms of IC(50) and K(i) determination on the hrBACE1-IMER. Thus, the hrBACE1-IMER has been confirmed as a valid tool for the throughput screening of different chemical entities with potency lower than 30μM for the fast hits' selection and for mode of action determination. Copyright © 2012 Elsevier B.V. All rights reserved.

Ranking targets in structure-based virtual screening of three-dimensional protein libraries: methods and problems.

PubMed

Kellenberger, Esther; Foata, Nicolas; Rognan, Didier

2008-05-01

Structure-based virtual screening is a promising tool to identify putative targets for a specific ligand. Instead of docking multiple ligands into a single protein cavity, a single ligand is docked in a collection of binding sites. In inverse screening, hits are in fact targets which have been prioritized within the pool of best ranked proteins. The target rate depends on specificity and promiscuity in protein-ligand interactions and, to a considerable extent, on the effectiveness of the scoring function, which still is the Achilles' heel of molecular docking. In the present retrospective study, virtual screening of the sc-PDB target library by GOLD docking was carried out for four compounds (biotin, 4-hydroxy-tamoxifen, 6-hydroxy-1,6-dihydropurine ribonucleoside, and methotrexate) of known sc-PDB targets and, several ranking protocols based on GOLD fitness score and topological molecular interaction fingerprint (IFP) comparison were evaluated. For the four investigated ligands, the fusion of GOLD fitness and two IFP scores allowed the recovery of most targets, including the rare proteins which are not readily suitable for statistical analysis, while significantly filtering out most false positive entries. The current survey suggests that selecting a small number of targets (<20) for experimental evaluation is achievable with a pure structure-based approach.

Height effects in real and virtual environments.

PubMed

Simeonov, Peter I; Hsiao, Hongwei; Dotson, Brian W; Ammons, Douglas E

2005-01-01

The study compared human perceptions of height, danger, and anxiety, as well as skin conductance and heart rate responses and postural instability effects, in real and virtual height environments. The 24 participants (12 men, 12 women), whose average age was 23.6 years, performed "lean-over-the-railing" and standing tasks on real and comparable virtual balconies, using a surround-screen virtual reality (SSVR) system. The results indicate that the virtual display of elevation provided realistic perceptual experience and induced some physiological responses and postural instability effects comparable to those found in a real environment. It appears that a simulation of elevated work environment in a SSVR system, although with reduced visual fidelity, is a valid tool for safety research. Potential applications of this study include the design of virtual environments that will help in safe evaluation of human performance at elevation, identification of risk factors leading to fall incidents, and assessment of new fall prevention strategies.

The Tropical Biominer Project: mining old sources for new drugs.

PubMed

Artiguenave, François; Lins, André; Maciel, Wesley Dias; Junior, Antonio Celso Caldeira; Nacif-Coelho, Carla; de Souza Linhares, Maria Margarida Ribeiro; de Oliveira, Guilherme Correa; Barbosa, Luis Humberto Rezende; Lopes, Júlio César Dias; Junior, Claudionor Nunes Coelho

2005-01-01

The Tropical Biominer Project is a recent initiative from the Federal University of Minas Gerais (UFMG) and the Oswaldo Cruz foundation, with the participation of the Biominas Foundation (Belo Horizonte, Minas Gerais, Brazil) and the start-up Homologix. The main objective of the project is to build a new resource for the chemogenomics research, on chemical compounds, with a strong emphasis on natural molecules. Adopted technologies include the search of information from structured, semi-structured, and non-structured documents (the last two from the web) and datamining tools in order to gather information from different sources. The database is the support for developing applications to find new potential treatments for parasitic infections by using virtual screening tools. We present here the midpoint of the project: the conception and implementation of the Tropical Biominer Database. This is a Federated Database designed to store data from different resources. Connected to the database, a web crawler is able to gather information from distinct, patented web sites and store them after automatic classification using datamining tools. Finally, we demonstrate the interest of the approach, by formulating new hypotheses on specific targets of a natural compound, violacein, using inferences from a Virtual Screening procedure.

Assessing Unilateral Spatial Neglect using advanced technologies: The potentiality of mobile virtual reality.

PubMed

Pallavicini, Federica; Pedroli, Elisa; Serino, Silvia; Dell'Isola, Andrea; Cipresso, Pietro; Cisari, Carlo; Riva, Giuseppe

2015-01-01

Unilateral Spatial Neglect, or neglect, is a common behavioral syndrome in patients following unilateral brain damage, such as stroke. In recent years, new technologies, such as computer-based tools and virtual reality have been used in order to solve some limitations of the traditional neglect evaluation. Within this perspective, also mobile devices such as tablets seems to be promising tools, being able to support interactive virtual environments and, at the same time, allowing to easily reproduce traditional paper-and-pencil test. In this context, the aim of our study was to investigate the potentiality of a new mobile application (Neglect App) designed and developed for tablet (iPad) for screening neglect symptoms. To address this objective, we divided a sample of 16 right-damaged patients according to the presence or absence of neglect and we administered assessment test in their traditional and Neglect App version. Results showed that the cancellation tests developed within Neglect App were equally effective to traditional paper-and-pencil tests (Line cancellation test and Star Cancellation test) in detecting neglect symptoms. Secondly, according to our results, the Neglect App Card Dealing task was more sensitive in detecting neglect symptoms than traditional functional task. Globally, results gives preliminary evidences supporting the feasibility of Neglect App for the screening of USN symptoms.

The virtual lover: variable and easily guided 3D fish animations as an innovative tool in mate-choice experiments with sailfin mollies-I. Design and implementation

PubMed Central

Smielik, Ievgen; Hütwohl, Jan-Marco; Gierszewski, Stefanie; Witte, Klaudia; Kuhnert, Klaus-Dieter

2017-01-01

Abstract Animal behavior researchers often face problems regarding standardization and reproducibility of their experiments. This has led to the partial substitution of live animals with artificial virtual stimuli. In addition to standardization and reproducibility, virtual stimuli open new options for researchers since they are easily changeable in morphology and appearance, and their behavior can be defined. In this article, a novel toolchain to conduct behavior experiments with fish is presented by a case study in sailfin mollies Poecilia latipinna. As the toolchain holds many different and novel features, it offers new possibilities for studies in behavioral animal research and promotes the standardization of experiments. The presented method includes options to design, animate, and present virtual stimuli to live fish. The designing tool offers an easy and user-friendly way to define size, coloration, and morphology of stimuli and moreover it is able to configure virtual stimuli randomly without any user influence. Furthermore, the toolchain brings a novel method to animate stimuli in a semiautomatic way with the help of a game controller. These created swimming paths can be applied to different stimuli in real time. A presentation tool combines models and swimming paths regarding formerly defined playlists, and presents the stimuli onto 2 screens. Experiments with live sailfin mollies validated the usage of the created virtual 3D fish models in mate-choice experiments. PMID:29491963

The virtual lover: variable and easily guided 3D fish animations as an innovative tool in mate-choice experiments with sailfin mollies-I. Design and implementation.

PubMed

Müller, Klaus; Smielik, Ievgen; Hütwohl, Jan-Marco; Gierszewski, Stefanie; Witte, Klaudia; Kuhnert, Klaus-Dieter

2017-02-01

Animal behavior researchers often face problems regarding standardization and reproducibility of their experiments. This has led to the partial substitution of live animals with artificial virtual stimuli. In addition to standardization and reproducibility, virtual stimuli open new options for researchers since they are easily changeable in morphology and appearance, and their behavior can be defined. In this article, a novel toolchain to conduct behavior experiments with fish is presented by a case study in sailfin mollies Poecilia latipinna . As the toolchain holds many different and novel features, it offers new possibilities for studies in behavioral animal research and promotes the standardization of experiments. The presented method includes options to design, animate, and present virtual stimuli to live fish. The designing tool offers an easy and user-friendly way to define size, coloration, and morphology of stimuli and moreover it is able to configure virtual stimuli randomly without any user influence. Furthermore, the toolchain brings a novel method to animate stimuli in a semiautomatic way with the help of a game controller. These created swimming paths can be applied to different stimuli in real time. A presentation tool combines models and swimming paths regarding formerly defined playlists, and presents the stimuli onto 2 screens. Experiments with live sailfin mollies validated the usage of the created virtual 3D fish models in mate-choice experiments.

Getting the Most out of PubChem for Virtual Screening

PubMed Central

Kim, Sunghwan

2016-01-01

Introduction With the emergence of the “big data” era, the biomedical research community has great interest in exploiting publicly available chemical information for drug discovery. PubChem is an example of public databases that provide a large amount of chemical information free of charge. Areas covered This article provides an overview of how PubChem’s data, tools, and services can be used for virtual screening and reviews recent publications that discuss important aspects of exploiting PubChem for drug discovery. Expert opinion PubChem offers comprehensive chemical information useful for drug discovery. It also provides multiple programmatic access routes, which are essential to build automated virtual screening pipelines that exploit PubChem data. In addition, PubChemRDF allows users to download PubChem data and load them into a local computing facility, facilitating data integration between PubChem and other resources. PubChem resources have been used in many studies for developing bioactivity and toxicity prediction models, discovering polypharmacologic (multi-target) ligands, and identifying new macromolecule targets of compounds (for drug-repurposing or off-target side effect prediction). These studies demonstrate the usefulness of PubChem as a key resource for computer-aided drug discovery and related area. PMID:27454129

Avalanche for shape and feature-based virtual screening with 3D alignment

NASA Astrophysics Data System (ADS)

Diller, David J.; Connell, Nancy D.; Welsh, William J.

2015-11-01

This report introduces a new ligand-based virtual screening tool called Avalanche that incorporates both shape- and feature-based comparison with three-dimensional (3D) alignment between the query molecule and test compounds residing in a chemical database. Avalanche proceeds in two steps. The first step is an extremely rapid shape/feature based comparison which is used to narrow the focus from potentially millions or billions of candidate molecules and conformations to a more manageable number that are then passed to the second step. The second step is a detailed yet still rapid 3D alignment of the remaining candidate conformations to the query conformation. Using the 3D alignment, these remaining candidate conformations are scored, re-ranked and presented to the user as the top hits for further visualization and evaluation. To provide further insight into the method, the results from two prospective virtual screens are presented which show the ability of Avalanche to identify hits from chemical databases that would likely be missed by common substructure-based or fingerprint-based search methods. The Avalanche method is extended to enable patent landscaping, i.e., structural refinements to improve the patentability of hits for deployment in drug discovery campaigns.

Dockres: a computer program that analyzes the output of virtual screening of small molecules

PubMed Central

2010-01-01

Background This paper describes a computer program named Dockres that is designed to analyze and summarize results of virtual screening of small molecules. The program is supplemented with utilities that support the screening process. Foremost among these utilities are scripts that run the virtual screening of a chemical library on a large number of processors in parallel. Methods Dockres and some of its supporting utilities are written Fortran-77; other utilities are written as C-shell scripts. They support the parallel execution of the screening. The current implementation of the program handles virtual screening with Autodock-3 and Autodock-4, but can be extended to work with the output of other programs. Results Analysis of virtual screening by Dockres led to both active and selective lead compounds. Conclusions Analysis of virtual screening was facilitated and enhanced by Dockres in both the authors' laboratories as well as laboratories elsewhere. PMID:20205801

Ligand-based virtual screening under partial shape constraints.

PubMed

von Behren, Mathias M; Rarey, Matthias

2017-04-01

Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure. The new method is integrated into the LBVS tool mRAISE providing multiple options for such constraints. The applied constraints can either be derived automatically from a protein-ligand complex structure or by manual selection of ligand atoms. In this way, the descriptor directly encodes the fit of a ligand into the binding site. Furthermore, the conservation of close contacts between the binding site surface and the query ligand can be enforced. We validated our new method on the DUD and DUD-E datasets. Although the statistical performance remains on the same level, detailed analysis reveal that for certain and especially very flexible targets a significant improvement can be achieved. This is further highlighted looking at the quality of calculated molecular alignments using the recently introduced mRAISE dataset. The new partial shape constraints improved the overall quality of molecular alignments especially for difficult targets with highly flexible or different sized molecules. The software tool mRAISE is freely available on Linux operating systems for evaluation purposes and academic use (see http://www.zbh.uni-hamburg.de/raise ).

Ligand-based virtual screening under partial shape constraints

NASA Astrophysics Data System (ADS)

von Behren, Mathias M.; Rarey, Matthias

2017-04-01

Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure. The new method is integrated into the LBVS tool mRAISE providing multiple options for such constraints. The applied constraints can either be derived automatically from a protein-ligand complex structure or by manual selection of ligand atoms. In this way, the descriptor directly encodes the fit of a ligand into the binding site. Furthermore, the conservation of close contacts between the binding site surface and the query ligand can be enforced. We validated our new method on the DUD and DUD-E datasets. Although the statistical performance remains on the same level, detailed analysis reveal that for certain and especially very flexible targets a significant improvement can be achieved. This is further highlighted looking at the quality of calculated molecular alignments using the recently introduced mRAISE dataset. The new partial shape constraints improved the overall quality of molecular alignments especially for difficult targets with highly flexible or different sized molecules. The software tool mRAISE is freely available on Linux operating systems for evaluation purposes and academic use (see http://www.zbh.uni-hamburg.de/raise).

Discovery of novel inhibitors for DHODH via virtual screening and X-ray crystallographic structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

McLean, Larry R.; Zhang, Ying; Degnen, William

2010-10-28

Amino-benzoic acid derivatives 1-4 were found to be inhibitors for DHODH by virtual screening, biochemical, and X-ray crystallographic studies. X-ray structures showed that 1 and 2 bind to DHODH as predicted by virtual screening, but 3 and 4 were found to be structurally different from the corresponding compounds initially identified by virtual screening.

Assessing local capacity to expand rural breast cancer screening and patient navigation: An iterative mixed-method tool.

PubMed

Inrig, Stephen J; Higashi, Robin T; Tiro, Jasmin A; Argenbright, Keith E; Lee, Simon J Craddock

2017-04-01

Despite federal funding for breast cancer screening, fragmented infrastructure and limited organizational capacity hinder access to the full continuum of breast cancer screening and clinical follow-up procedures among rural-residing women. We proposed a regional hub-and-spoke model, partnering with local providers to expand access across North Texas. We describe development and application of an iterative, mixed-method tool to assess county capacity to conduct community outreach and/or patient navigation in a partnership model. Our tool combined publicly-available quantitative data with qualitative assessments during site visits and semi-structured interviews. Application of our tool resulted in shifts in capacity designation in 10 of 17 county partners: 8 implemented local outreach with hub navigation; 9 relied on the hub for both outreach and navigation. Key factors influencing capacity: (1) formal linkages between partner organizations; (2) inter-organizational relationships; (3) existing clinical service protocols; (4) underserved populations. Qualitative data elucidate how our tool captured these capacity changes. Our capacity assessment tool enabled the hub to establish partnerships with county organizations by tailoring support to local capacity and needs. Absent a vertically integrated provider network for preventive services in these rural counties, our tool facilitated a virtually integrated regional network to extend access to breast cancer screening to underserved women. Copyright © 2016 Elsevier Ltd. All rights reserved.

SABRE: ligand/structure-based virtual screening approach using consensus molecular-shape pattern recognition.

PubMed

Wei, Ning-Ning; Hamza, Adel

2014-01-27

We present an efficient and rational ligand/structure shape-based virtual screening approach combining our previous ligand shape-based similarity SABRE (shape-approach-based routines enhanced) and the 3D shape of the receptor binding site. Our approach exploits the pharmacological preferences of a number of known active ligands to take advantage of the structural diversities and chemical similarities, using a linear combination of weighted molecular shape density. Furthermore, the algorithm generates a consensus molecular-shape pattern recognition that is used to filter and place the candidate structure into the binding pocket. The descriptor pool used to construct the consensus molecular-shape pattern consists of four dimensional (4D) fingerprints generated from the distribution of conformer states available to a molecule and the 3D shapes of a set of active ligands computed using SABRE software. The virtual screening efficiency of SABRE was validated using the Database of Useful Decoys (DUD) and the filtered version (WOMBAT) of 10 DUD targets. The ligand/structure shape-based similarity SABRE algorithm outperforms several other widely used virtual screening methods which uses the data fusion of multiscreening tools (2D and 3D fingerprints) and demonstrates a superior early retrieval rate of active compounds (EF(0.1%) = 69.0% and EF(1%) = 98.7%) from a large size of ligand database (∼95,000 structures). Therefore, our developed similarity approach can be of particular use for identifying active compounds that are similar to reference molecules and predicting activity against other targets (chemogenomics). An academic license of the SABRE program is available on request.

Optical 3D surface digitizing in forensic medicine: 3D documentation of skin and bone injuries.

PubMed

Thali, Michael J; Braun, Marcel; Dirnhofer, Richard

2003-11-26

Photography process reduces a three-dimensional (3D) wound to a two-dimensional level. If there is a need for a high-resolution 3D dataset of an object, it needs to be three-dimensionally scanned. No-contact optical 3D digitizing surface scanners can be used as a powerful tool for wound and injury-causing instrument analysis in trauma cases. The 3D skin wound and a bone injury documentation using the optical scanner Advanced TOpometric Sensor (ATOS II, GOM International, Switzerland) will be demonstrated using two illustrative cases. Using this 3D optical digitizing method the wounds (the virtual 3D computer model of the skin and the bone injuries) and the virtual 3D model of the injury-causing tool are graphically documented in 3D in real-life size and shape and can be rotated in the CAD program on the computer screen. In addition, the virtual 3D models of the bone injuries and tool can now be compared in a 3D CAD program against one another in virtual space, to see if there are matching areas. Further steps in forensic medicine will be a full 3D surface documentation of the human body and all the forensic relevant injuries using optical 3D scanners.

Domain-Specific QSAR Models for Identifying Potential Estrogenic Activity of Phenols (FutureTox III)

EPA Science Inventory

Computational tools can be used for efficient evaluation of untested chemicals for their ability to disrupt the endocrine system. We have employed previously developed global QSAR models that were trained and validated on the ToxCast/Tox21 ER assay data for virtual screening of a...

Ligand-guided optimization of CXCR4 homology models for virtual screening using a multiple chemotype approach

NASA Astrophysics Data System (ADS)

Neves, Marco A. C.; Simões, Sérgio; Sá e Melo, M. Luisa

2010-12-01

CXCR4 is a G-protein coupled receptor for CXCL12 that plays an important role in human immunodeficiency virus infection, cancer growth and metastasization, immune cell trafficking and WHIM syndrome. In the absence of an X-ray crystal structure, theoretical modeling of the CXCR4 receptor remains an important tool for structure-function analysis and to guide the discovery of new antagonists with potential clinical use. In this study, the combination of experimental data and molecular modeling approaches allowed the development of optimized ligand-receptor models useful for elucidation of the molecular determinants of small molecule binding and functional antagonism. The ligand-guided homology modeling approach used in this study explicitly re-shaped the CXCR4 binding pocket in order to improve discrimination between known CXCR4 antagonists and random decoys. Refinement based on multiple test-sets with small compounds from single chemotypes provided the best early enrichment performance. These results provide an important tool for structure-based drug design and virtual ligand screening of new CXCR4 antagonists.

Automated recycling of chemistry for virtual screening and library design.

PubMed

Vainio, Mikko J; Kogej, Thierry; Raubacher, Florian

2012-07-23

An early stage drug discovery project needs to identify a number of chemically diverse and attractive compounds. These hit compounds are typically found through high-throughput screening campaigns. The diversity of the chemical libraries used in screening is therefore important. In this study, we describe a virtual high-throughput screening system called Virtual Library. The system automatically "recycles" validated synthetic protocols and available starting materials to generate a large number of virtual compound libraries, and allows for fast searches in the generated libraries using a 2D fingerprint based screening method. Virtual Library links the returned virtual hit compounds back to experimental protocols to quickly assess the synthetic accessibility of the hits. The system can be used as an idea generator for library design to enrich the screening collection and to explore the structure-activity landscape around a specific active compound.

Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description.

PubMed

Spyrakis, Francesca; Cavasotto, Claudio N

2015-10-01

Structure-based virtual screening is currently an established tool in drug lead discovery projects. Although in the last years the field saw an impressive progress in terms of algorithm development, computational performance, and retrospective and prospective applications in ligand identification, there are still long-standing challenges where further improvement is needed. In this review, we consider the conceptual frame, state-of-the-art and recent developments of three critical "structural" issues in structure-based drug lead discovery: the use of homology modeling to accurately model the binding site when no experimental structures are available, the necessity of accounting for the dynamics of intrinsically flexible systems as proteins, and the importance of considering active site water molecules in lead identification and optimization campaigns. Copyright © 2015 Elsevier Inc. All rights reserved.

Knowledge-driven lead discovery.

PubMed

Pirard, Bernard

2005-11-01

Virtual screening encompasses several computational approaches which have proven valuable for identifying novel leads. These approaches rely on available information. Herein, we review recent successful applications of virtual screening. The extension of virtual screening methodologies to target families is also briefly discussed.

Teaching cardiopulmonary auscultation in workshops using a virtual patient simulation technology - A pilot study.

PubMed

Pereira, D; Gomes, P; Faria, S; Cruz-Correia, R; Coimbra, M

2016-08-01

Auscultation is currently both a powerful screening tool, providing a cheap and quick initial assessment of a patient's clinical condition, and a hard skill to master. The teaching of auscultation in Universities is today reduced to an unsuitable number of hours. Virtual patient simulators can potentially mitigate this problem, by providing an interesting high-quality alternative to teaching with real patients or patient simulators. In this paper we evaluate the pedagogical impact of using a virtual patient simulation technology in a short workshop format for medical students, training them to detect cardiac pathologies. Results showed a significant improvement (+16%) in the differentiation between normal and pathological cases, although longer duration formats seem to be needed to accurately identify specific pathologies.

Virtual-Instrument-Based Online Monitoring System for Hands-on Laboratory Experiment of Partial Discharges

ERIC Educational Resources Information Center

Karmakar, Subrata

2017-01-01

Online monitoring of high-voltage (HV) equipment is a vital tool for early detection of insulation failure. Most insulation failures are caused by partial discharges (PDs) inside the HV equipment. Because of the very high cost of establishing HV equipment facility and the limitations of electromagnetic interference-screened laboratories, only a…

DOVIS 2.0: An Efficient and Easy to Use Parallel Virtual Screening Tool Based on AutoDock 4.0

DTIC Science & Technology

2008-09-08

under the GNU General Public License. Background Molecular docking is a computational method that pre- dicts how a ligand interacts with a receptor...Hence, it is an important tool in studying receptor-ligand interactions and plays an essential role in drug design. Particularly, molecular docking has...libraries from OpenBabel and setup a molecular data structure as a C++ object in our program. This makes handling of molecular structures (e.g., atoms

Mastoidectomy performance assessment of virtual simulation training using final-product analysis.

PubMed

Andersen, Steven A W; Cayé-Thomasen, Per; Sørensen, Mads S

2015-02-01

The future development of integrated automatic assessment in temporal bone virtual surgical simulators calls for validation against currently established assessment tools. This study aimed to explore the relationship between mastoidectomy final-product performance assessment in virtual simulation and traditional dissection training. Prospective trial with blinding. A total of 34 novice residents performed a mastoidectomy on the Visible Ear Simulator and on a cadaveric temporal bone. Two blinded senior otologists assessed the final-product performance using a modified Welling scale. The simulator gathered basic metrics on time, steps, and volumes in relation to the on-screen tutorial and collisions with vital structures. Substantial inter-rater reliability (kappa = 0.77) for virtual simulation and moderate inter-rater reliability (kappa = 0.59) for dissection final-product assessment was found. The simulation and dissection performance scores had significant correlation (P = .014). None of the basic simulator metrics correlated significantly with the final-product score except for number of steps completed in the simulator. A modified version of a validated final-product performance assessment tool can be used to assess mastoidectomy on virtual temporal bones. Performance assessment of virtual mastoidectomy could potentially save the use of cadaveric temporal bones for more advanced training when a basic level of competency in simulation has been achieved. NA. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

HPLC studio: a novel software utility to perform HPLC chromatogram comparison for screening purposes.

PubMed

García, J B; Tormo, José R

2003-06-01

A new tool, HPLC Studio, was developed for the comparison of high-performance liquid chromatography (HPLC) chromatograms from microbial extracts. The new utility makes it possible to create a virtual chromatogram by mixing up to 20 individual chromatograms. The virtual chromatogram is the first step in establishing a ranking of the microbial fermentation conditions based on either the area or diversity of HPLC peaks. The utility was used to maximize the diversity of secondary metabolites tested from a microorganism and therefore increase the chances of finding new lead compounds in a drug discovery program.

Developing science gateways for drug discovery in a grid environment.

PubMed

Pérez-Sánchez, Horacio; Rezaei, Vahid; Mezhuyev, Vitaliy; Man, Duhu; Peña-García, Jorge; den-Haan, Helena; Gesing, Sandra

2016-01-01

Methods for in silico screening of large databases of molecules increasingly complement and replace experimental techniques to discover novel compounds to combat diseases. As these techniques become more complex and computationally costly we are faced with an increasing problem to provide the research community of life sciences with a convenient tool for high-throughput virtual screening on distributed computing resources. To this end, we recently integrated the biophysics-based drug-screening program FlexScreen into a service, applicable for large-scale parallel screening and reusable in the context of scientific workflows. Our implementation is based on Pipeline Pilot and Simple Object Access Protocol and provides an easy-to-use graphical user interface to construct complex workflows, which can be executed on distributed computing resources, thus accelerating the throughput by several orders of magnitude.

Virtual reality hardware for use in interactive 3D data fusion and visualization

NASA Astrophysics Data System (ADS)

Gourley, Christopher S.; Abidi, Mongi A.

1997-09-01

Virtual reality has become a tool for use in many areas of research. We have designed and built a VR system for use in range data fusion and visualization. One major VR tool is the CAVE. This is the ultimate visualization tool, but comes with a large price tag. Our design uses a unique CAVE whose graphics are powered by a desktop computer instead of a larger rack machine making it much less costly. The system consists of a screen eight feet tall by twenty-seven feet wide giving a variable field-of-view currently set at 160 degrees. A silicon graphics Indigo2 MaxImpact with the impact channel option is used for display. This gives the capability to drive three projectors at a resolution of 640 by 480 for use in displaying the virtual environment and one 640 by 480 display for a user control interface. This machine is also the first desktop package which has built-in hardware texture mapping. This feature allows us to quickly fuse the range and intensity data and other multi-sensory data. The final goal is a complete 3D texture mapped model of the environment. A dataglove, magnetic tracker, and spaceball are to be used for manipulation of the data and navigation through the virtual environment. This system gives several users the ability to interactively create 3D models from multiple range images.

Shape-Based Virtual Screening with Volumetric Aligned Molecular Shapes

PubMed Central

Koes, David Ryan; Camacho, Carlos J.

2014-01-01

Shape-based virtual screening is an established and effective method for identifying small molecules that are similar in shape and function to a reference ligand. We describe a new method of shape-based virtual screening, volumetric aligned molecular shapes (VAMS). VAMS uses efficient data structures to encode and search molecular shapes. We demonstrate that VAMS is an effective method for shape-based virtual screening and that it can be successfully used as a pre-filter to accelerate more computationally demanding search algorithms. Unique to VAMS is a novel minimum/maximum shape constraint query for precisely specifying the desired molecular shape. Shape constraint searches in VAMS are particularly efficient and millions of shapes can be searched in a fraction of a second. We compare the performance of VAMS with two other shape-based virtual screening algorithms a benchmark of 102 protein targets consisting of more than 32 million molecular shapes and find that VAMS provides a competitive trade-off between run-time performance and virtual screening performance. PMID:25049193

DPubChem: a web tool for QSAR modeling and high-throughput virtual screening.

PubMed

Soufan, Othman; Ba-Alawi, Wail; Magana-Mora, Arturo; Essack, Magbubah; Bajic, Vladimir B

2018-06-14

High-throughput screening (HTS) performs the experimental testing of a large number of chemical compounds aiming to identify those active in the considered assay. Alternatively, faster and cheaper methods of large-scale virtual screening are performed computationally through quantitative structure-activity relationship (QSAR) models. However, the vast amount of available HTS heterogeneous data and the imbalanced ratio of active to inactive compounds in an assay make this a challenging problem. Although different QSAR models have been proposed, they have certain limitations, e.g., high false positive rates, complicated user interface, and limited utilization options. Therefore, we developed DPubChem, a novel web tool for deriving QSAR models that implement the state-of-the-art machine-learning techniques to enhance the precision of the models and enable efficient analyses of experiments from PubChem BioAssay database. DPubChem also has a simple interface that provides various options to users. DPubChem predicted active compounds for 300 datasets with an average geometric mean and F 1 score of 76.68% and 76.53%, respectively. Furthermore, DPubChem builds interaction networks that highlight novel predicted links between chemical compounds and biological assays. Using such a network, DPubChem successfully suggested a novel drug for the Niemann-Pick type C disease. DPubChem is freely available at www.cbrc.kaust.edu.sa/dpubchem .

[Chemical databases and virtual screening].

PubMed

Rognan, Didier; Bonnet, Pascal

2014-12-01

A prerequisite to any virtual screening is the definition of compound libraries to be screened. As we describe here, various sources are available. The selection of the proper library is usually project-dependent but at least as important as the screening method itself. This review details the main compound libraries that are available for virtual screening and guide the reader to the best possible selection according to its needs. © 2014 médecine/sciences – Inserm.

Virtual reality as a screening tool for sports concussion in adolescents.

PubMed

Nolin, Pierre; Stipanicic, Annie; Henry, Mylène; Joyal, Christian C; Allain, Philippe

2012-01-01

There is controversy surrounding the cognitive effects of sports concussion. This study aimed to verify whether the technique of virtual reality could aid in the identification of attention and inhibition deficits in adolescents. A prospective design was used to assess 25 sports-concussed and 25 non-sports-concussed adolescents enrolled in a sport and education programme. Participants were evaluated in immersive virtual reality via ClinicaVR: Classroom-CPT and in real life via the traditional VIGIL-CPT. The neuropsychological assessment using virtual reality showed greater sensitivity to the subtle effects of sports concussion compared to the traditional test, which showed no difference between groups. The results also demonstrated that the sports concussion group reported more symptoms of cybersickness and more intense cybersickness than the control group. Sports concussion was associated with subtle deficits in attention and inhibition. However, further studies are needed to support these results.

CSBB-ConeExclusion, adapting structure based solution virtual screening to libraries on solid support.

PubMed

Shave, Steven; Auer, Manfred

2013-12-23

Combinatorial chemical libraries produced on solid support offer fast and cost-effective access to a large number of unique compounds. If such libraries are screened directly on-bead, the speed at which chemical space can be explored by chemists is much greater than that addressable using solution based synthesis and screening methods. Solution based screening has a large supporting body of software such as structure-based virtual screening tools which enable the prediction of protein-ligand complexes. Use of these techniques to predict the protein bound complexes of compounds synthesized on solid support neglects to take into account the conjugation site on the small molecule ligand. This may invalidate predicted binding modes, the linker may be clashing with protein atoms. We present CSBB-ConeExclusion, a methodology and computer program which provides a measure of the applicability of solution dockings to solid support. Output is given in the form of statistics for each docking pose, a unique 2D visualization method which can be used to determine applicability at a glance, and automatically generated PyMol scripts allowing visualization of protein atom incursion into a defined exclusion volume. CSBB-ConeExclusion is then exemplarically used to determine the optimum attachment point for a purine library targeting cyclin-dependent kinase 2 CDK2.

Ultrafast protein structure-based virtual screening with Panther

NASA Astrophysics Data System (ADS)

Niinivehmas, Sanna P.; Salokas, Kari; Lätti, Sakari; Raunio, Hannu; Pentikäinen, Olli T.

2015-10-01

Molecular docking is by far the most common method used in protein structure-based virtual screening. This paper presents Panther, a novel ultrafast multipurpose docking tool. In Panther, a simple shape-electrostatic model of the ligand-binding area of the protein is created by utilizing the protein crystal structure. The features of the possible ligands are then compared to the model by using a similarity search algorithm. On average, one ligand can be processed in a few minutes by using classical docking methods, whereas using Panther processing takes <1 s. The presented Panther protocol can be used in several applications, such as speeding up the early phases of drug discovery projects, reducing the number of failures in the clinical phase of the drug development process, and estimating the environmental toxicity of chemicals. Panther-code is available in our web pages (http://www.jyu.fi/panther) free of charge after registration.

Ultrafast protein structure-based virtual screening with Panther.

PubMed

Niinivehmas, Sanna P; Salokas, Kari; Lätti, Sakari; Raunio, Hannu; Pentikäinen, Olli T

2015-10-01

Molecular docking is by far the most common method used in protein structure-based virtual screening. This paper presents Panther, a novel ultrafast multipurpose docking tool. In Panther, a simple shape-electrostatic model of the ligand-binding area of the protein is created by utilizing the protein crystal structure. The features of the possible ligands are then compared to the model by using a similarity search algorithm. On average, one ligand can be processed in a few minutes by using classical docking methods, whereas using Panther processing takes <1 s. The presented Panther protocol can be used in several applications, such as speeding up the early phases of drug discovery projects, reducing the number of failures in the clinical phase of the drug development process, and estimating the environmental toxicity of chemicals. Panther-code is available in our web pages (http://www.jyu.fi/panther) free of charge after registration.

In-silico guided discovery of novel CCR9 antagonists

NASA Astrophysics Data System (ADS)

Zhang, Xin; Cross, Jason B.; Romero, Jan; Heifetz, Alexander; Humphries, Eric; Hall, Katie; Wu, Yuchuan; Stucka, Sabrina; Zhang, Jing; Chandonnet, Haoqun; Lippa, Blaise; Ryan, M. Dominic; Baber, J. Christian

2018-03-01

Antagonism of CCR9 is a promising mechanism for treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. There is limited experimental data on CCR9 and its ligands, complicating efforts to identify new small molecule antagonists. We present here results of a successful virtual screening and rational hit-to-lead campaign that led to the discovery and initial optimization of novel CCR9 antagonists. This work uses a novel data fusion strategy to integrate the output of multiple computational tools, such as 2D similarity search, shape similarity, pharmacophore searching, and molecular docking, as well as the identification and incorporation of privileged chemokine fragments. The application of various ranking strategies, which combined consensus and parallel selection methods to achieve a balance of enrichment and novelty, resulted in 198 virtual screening hits in total, with an overall hit rate of 18%. Several hits were developed into early leads through targeted synthesis and purchase of analogs.

Footprinting of Inhibitor Interactions of In Silico Identified Inhibitors of Trypanothione Reductase of Leishmania Parasite

PubMed Central

Venkatesan, Santhosh K.; Dubey, Vikash Kumar

2012-01-01

Structure-based virtual screening of NCI Diversity set II compounds was performed to indentify novel inhibitor scaffolds of trypanothione reductase (TR) from Leishmania infantum. The top 50 ranked hits were clustered using the AuPoSOM tool. Majority of the top-ranked compounds were Tricyclic. Clustering of hits yielded four major clusters each comprising varying number of subclusters differing in their mode of binding and orientation in the active site. Moreover, for the first time, we report selected alkaloids and dibenzothiazepines as inhibitors of Leishmania infantum TR. The mode of binding observed among the clusters also potentiates the probable in vitro inhibition kinetics and aids in defining key interaction which might contribute to the inhibition of enzymatic reduction of T[S] 2. The method provides scope for automation and integration into the virtual screening process employing docking softwares, for clustering the small molecule inhibitors based upon protein-ligand interactions. PMID:22550471

Identification of new allosteric sites and modulators of AChE through computational and experimental tools.

PubMed

Roca, Carlos; Requena, Carlos; Sebastián-Pérez, Víctor; Malhotra, Sony; Radoux, Chris; Pérez, Concepción; Martinez, Ana; Antonio Páez, Juan; Blundell, Tom L; Campillo, Nuria E

2018-12-01

Allosteric sites on proteins are targeted for designing more selective inhibitors of enzyme activity and to discover new functions. Acetylcholinesterase (AChE), which is most widely known for the hydrolysis of the neurotransmitter acetylcholine, has a peripheral allosteric subsite responsible for amyloidosis in Alzheimer's disease through interaction with amyloid β-peptide. However, AChE plays other non-hydrolytic functions. Here, we identify and characterise using computational tools two new allosteric sites in AChE, which have allowed us to identify allosteric inhibitors by virtual screening guided by structure-based and fragment hotspot strategies. The identified compounds were also screened for in vitro inhibition of AChE and three were observed to be active. Further experimental (kinetic) and computational (molecular dynamics) studies have been performed to verify the allosteric activity. These new compounds may be valuable pharmacological tools in the study of non-cholinergic functions of AChE.

Validation of the Arab Youth Mental Health scale as a screening tool for depression/anxiety in Lebanese children

PubMed Central

2011-01-01

Background Early detection of common mental disorders, such as depression and anxiety, among children and adolescents requires the use of validated, culturally sensitive, and developmentally appropriate screening instruments. The Arab region has a high proportion of youth, yet Arabic-language screening instruments for mental disorders among this age group are virtually absent. Methods We carried out construct and clinical validation on the recently-developed Arab Youth Mental Health (AYMH) scale as a screening tool for depression/anxiety. The scale was administered with 10-14 year old children attending a social service center in Beirut, Lebanon (N = 153). The clinical assessment was conducted by a child and adolescent clinical psychiatrist employing the DSM IV criteria. We tested the scale's sensitivity, specificity, and internal consistency. Results Scale scores were generally significantly associated with how participants responded to standard questions on health, mental health, and happiness, indicating good construct validity. The results revealed that the scale exhibited good internal consistency (Cronbach's alpha = 0.86) and specificity (79%). However, it exhibited moderate sensitivity for girls (71%) and poor sensitivity for boys (50%). Conclusions The AYMH scale is useful as a screening tool for general mental health states and a valid screening instrument for common mental disorders among girls. It is not a valid instrument for detecting depression and anxiety among boys in an Arab culture. PMID:21435213

Human responses to augmented virtual scaffolding models.

PubMed

Hsiao, Hongwei; Simeonov, Peter; Dotson, Brian; Ammons, Douglas; Kau, Tsui-Ying; Chiou, Sharon

2005-08-15

This study investigated the effect of adding real planks, in virtual scaffolding models of elevation, on human performance in a surround-screen virtual reality (SSVR) system. Twenty-four construction workers and 24 inexperienced controls performed walking tasks on real and virtual planks at three virtual heights (0, 6 m, 12 m) and two scaffolding-platform-width conditions (30, 60 cm). Gait patterns, walking instability measurements and cardiovascular reactivity were assessed. The results showed differences in human responses to real vs. virtual planks in walking patterns, instability score and heart-rate inter-beat intervals; it appeared that adding real planks in the SSVR virtual scaffolding model enhanced the quality of SSVR as a human - environment interface research tool. In addition, there were significant differences in performance between construction workers and the control group. The inexperienced participants were more unstable as compared to construction workers. Both groups increased their stride length with repetitions of the task, indicating a possibly confidence- or habit-related learning effect. The practical implications of this study are in the adoption of augmented virtual models of elevated construction environments for injury prevention research, and the development of programme for balance-control training to reduce the risk of falls at elevation before workers enter a construction job.

Using Docker Compose for the Simple Deployment of an Integrated Drug Target Screening Platform.

PubMed

List, Markus

2017-06-10

Docker virtualization allows for software tools to be executed in an isolated and controlled environment referred to as a container. In Docker containers, dependencies are provided exactly as intended by the developer and, consequently, they simplify the distribution of scientific software and foster reproducible research. The Docker paradigm is that each container encapsulates one particular software tool. However, to analyze complex biomedical data sets, it is often necessary to combine several software tools into elaborate workflows. To address this challenge, several Docker containers need to be instantiated and properly integrated, which complicates the software deployment process unnecessarily. Here, we demonstrate how an extension to Docker, Docker compose, can be used to mitigate these problems by providing a unified setup routine that deploys several tools in an integrated fashion. We demonstrate the power of this approach by example of a Docker compose setup for a drug target screening platform consisting of five integrated web applications and shared infrastructure, deployable in just two lines of codes.

Virtual Screening of Phytochemicals to Novel Target (HAT) Rtt109 in Pneumocystis Jirovecii using Bioinformatics Tools.

PubMed

Sugumar, Ramya; Adithavarman, Abhinand Ponneri; Dakshinamoorthi, Anusha; David, Darling Chellathai; Ragunath, Padmavathi Kannan

2016-03-01

Pneumocystis jirovecii is a fungus that causes Pneumocystis pneumonia in HIV and other immunosuppressed patients. Treatment of Pneumocystis pneumonia with the currently available antifungals is challenging and associated with considerable adverse effects. There is a need to develop drugs against novel targets with minimal human toxicities. Histone Acetyl Transferase (HAT) Rtt109 is a potential therapeutic target in Pneumocystis jirovecii species. HAT is linked to transcription and is required to acetylate conserved lysine residues on histone proteins by transferring an acetyl group from acetyl CoA to form e-N-acetyl lysine. Therefore, inhibitors of HAT can be useful therapeutic options in Pneumocystis pneumonia. To screen phytochemicals against (HAT) Rtt109 using bioinformatics tool. The tertiary structure of Pneumocystis jirovecii (HAT) Rtt109 was modeled by Homology Modeling. The ideal template for modeling was obtained by performing Psi BLAST of the protein sequence. Rtt109-AcCoA/Vps75 protein from Saccharomyces cerevisiae (PDB structure 3Q35) was chosen as the template. The target protein was modeled using Swiss Modeler and validated using Ramachandran plot and Errat 2. Comprehensive text mining was performed to identify phytochemical compounds with antipneumonia and fungicidal properties and these compounds were filtered based on Lipinski's Rule of 5. The chosen compounds were subjected to virtual screening against the target protein (HAT) Rtt109 using Molegro Virtual Docker 4.5. Osiris Property Explorer and Open Tox Server were used to predict ADME-T properties of the chosen phytochemicals. Tertiary structure model of HAT Rtt 109 had a ProSA score of -6.57 and Errat 2 score of 87.34. Structure validation analysis by Ramachandran plot for the model revealed 97% of amino acids were in the favoured region. Of all the phytochemicals subjected to virtual screening against the target protein (HAT) Rtt109, baicalin exhibited highest binding affinity towards the target protein as indicated by the Molegro score of 130.68 and formed 16 H-bonds. The ADME-T property prediction revealed that baicalin was non-mutagenic, non-tumorigenic and had a drug likeness score of 0.87. Baicalin has good binding with Rtt 109 in Pneumocystis jirovecii and can be considered as a novel and valuable treatment option for Pneumocystis pneumonia patients after subjecting it to invivo and invitro studies.

Virtual Screening of Phytochemicals to Novel Target (HAT) Rtt109 in Pneumocystis Jirovecii using Bioinformatics Tools

PubMed Central

Adithavarman, Abhinand Ponneri; Dakshinamoorthi, Anusha; David, Darling Chellathai; Ragunath, Padmavathi Kannan

2016-01-01

Introduction Pneumocystis jirovecii is a fungus that causes Pneumocystis pneumonia in HIV and other immunosuppressed patients. Treatment of Pneumocystis pneumonia with the currently available antifungals is challenging and associated with considerable adverse effects. There is a need to develop drugs against novel targets with minimal human toxicities. Histone Acetyl Transferase (HAT) Rtt109 is a potential therapeutic target in Pneumocystis jirovecii species. HAT is linked to transcription and is required to acetylate conserved lysine residues on histone proteins by transferring an acetyl group from acetyl CoA to form e-N-acetyl lysine. Therefore, inhibitors of HAT can be useful therapeutic options in Pneumocystis pneumonia. Aim To screen phytochemicals against (HAT) Rtt109 using bioinformatics tool. Materials and Methods The tertiary structure of Pneumocystis jirovecii (HAT) Rtt109 was modeled by Homology Modeling. The ideal template for modeling was obtained by performing Psi BLAST of the protein sequence. Rtt109-AcCoA/Vps75 protein from Saccharomyces cerevisiae (PDB structure 3Q35) was chosen as the template. The target protein was modeled using Swiss Modeler and validated using Ramachandran plot and Errat 2. Comprehensive text mining was performed to identify phytochemical compounds with antipneumonia and fungicidal properties and these compounds were filtered based on Lipinski’s Rule of 5. The chosen compounds were subjected to virtual screening against the target protein (HAT) Rtt109 using Molegro Virtual Docker 4.5. Osiris Property Explorer and Open Tox Server were used to predict ADME-T properties of the chosen phytochemicals. Results Tertiary structure model of HAT Rtt 109 had a ProSA score of -6.57 and Errat 2 score of 87.34. Structure validation analysis by Ramachandran plot for the model revealed 97% of amino acids were in the favoured region. Of all the phytochemicals subjected to virtual screening against the target protein (HAT) Rtt109, baicalin exhibited highest binding affinity towards the target protein as indicated by the Molegro score of 130.68 and formed 16 H-bonds. The ADME-T property prediction revealed that baicalin was non-mutagenic, non-tumorigenic and had a drug likeness score of 0.87. Conclusion Baicalin has good binding with Rtt 109 in Pneumocystis jirovecii and can be considered as a novel and valuable treatment option for Pneumocystis pneumonia patients after subjecting it to invivo and invitro studies. PMID:27134887

Simultaneous virtual prediction of anti-Escherichia coli activities and ADMET profiles: A chemoinformatic complementary approach for high-throughput screening.

PubMed

Speck-Planche, Alejandro; Cordeiro, M N D S

2014-02-10

Escherichia coli remains one of the principal pathogens that cause nosocomial infections, medical conditions that are increasingly common in healthcare facilities. E. coli is intrinsically resistant to many antibiotics, and multidrug-resistant strains have emerged recently. Chemoinformatics has been a great ally of experimental methodologies such as high-throughput screening, playing an important role in the discovery of effective antibacterial agents. However, there is no approach that can design safer anti-E. coli agents, because of the multifactorial nature and complexity of bacterial diseases and the lack of desirable ADMET (absorption, distribution, metabolism, elimination, and toxicity) profiles as a major cause of disapproval of drugs. In this work, we introduce the first multitasking model based on quantitative-structure biological effect relationships (mtk-QSBER) for simultaneous virtual prediction of anti-E. coli activities and ADMET properties of drugs and/or chemicals under many experimental conditions. The mtk-QSBER model was developed from a large and heterogeneous data set of more than 37800 cases, exhibiting overall accuracies of >95% in both training and prediction (validation) sets. The utility of our mtk-QSBER model was demonstrated by performing virtual prediction of properties for the investigational drug avarofloxacin (AVX) under 260 different experimental conditions. Results converged with the experimental evidence, confirming the remarkable anti-E. coli activities and safety of AVX. Predictions also showed that our mtk-QSBER model can be a promising computational tool for virtual screening of desirable anti-E. coli agents, and this chemoinformatic approach could be extended to the search for safer drugs with defined pharmacological activities.

DEC Ada interface to Screen Management Guidelines (SMG)

NASA Technical Reports Server (NTRS)

Laomanachareon, Somsak; Lekkos, Anthony A.

1986-01-01

DEC's Screen Management Guidelines are the Run-Time Library procedures that perform terminal-independent screen management functions on a VT100-class terminal. These procedures assist users in designing, composing, and keeping track of complex images on a video screen. There are three fundamental elements in the screen management model: the pasteboard, the virtual display, and the virtual keyboard. The pasteboard is like a two-dimensional area on which a user places and manipulates screen displays. The virtual display is a rectangular part of the terminal screen to which a program writes data with procedure calls. The virtual keyboard is a logical structure for input operation associated with a physical keyboard. SMG can be called by all major VAX languages. Through Ada, predefined language Pragmas are used to interface with SMG. These features and elements of SMG are briefly discussed.

Performance of machine-learning scoring functions in structure-based virtual screening.

PubMed

Wójcikowski, Maciej; Ballester, Pedro J; Siedlecki, Pawel

2017-04-25

Classical scoring functions have reached a plateau in their performance in virtual screening and binding affinity prediction. Recently, machine-learning scoring functions trained on protein-ligand complexes have shown great promise in small tailored studies. They have also raised controversy, specifically concerning model overfitting and applicability to novel targets. Here we provide a new ready-to-use scoring function (RF-Score-VS) trained on 15 426 active and 893 897 inactive molecules docked to a set of 102 targets. We use the full DUD-E data sets along with three docking tools, five classical and three machine-learning scoring functions for model building and performance assessment. Our results show RF-Score-VS can substantially improve virtual screening performance: RF-Score-VS top 1% provides 55.6% hit rate, whereas that of Vina only 16.2% (for smaller percent the difference is even more encouraging: RF-Score-VS top 0.1% achieves 88.6% hit rate for 27.5% using Vina). In addition, RF-Score-VS provides much better prediction of measured binding affinity than Vina (Pearson correlation of 0.56 and -0.18, respectively). Lastly, we test RF-Score-VS on an independent test set from the DEKOIS benchmark and observed comparable results. We provide full data sets to facilitate further research in this area (http://github.com/oddt/rfscorevs) as well as ready-to-use RF-Score-VS (http://github.com/oddt/rfscorevs_binary).

Improved genome-scale multi-target virtual screening via a novel collaborative filtering approach to cold-start problem

PubMed Central

Lim, Hansaim; Gray, Paul; Xie, Lei; Poleksic, Aleksandar

2016-01-01

Conventional one-drug-one-gene approach has been of limited success in modern drug discovery. Polypharmacology, which focuses on searching for multi-targeted drugs to perturb disease-causing networks instead of designing selective ligands to target individual proteins, has emerged as a new drug discovery paradigm. Although many methods for single-target virtual screening have been developed to improve the efficiency of drug discovery, few of these algorithms are designed for polypharmacology. Here, we present a novel theoretical framework and a corresponding algorithm for genome-scale multi-target virtual screening based on the one-class collaborative filtering technique. Our method overcomes the sparseness of the protein-chemical interaction data by means of interaction matrix weighting and dual regularization from both chemicals and proteins. While the statistical foundation behind our method is general enough to encompass genome-wide drug off-target prediction, the program is specifically tailored to find protein targets for new chemicals with little to no available interaction data. We extensively evaluate our method using a number of the most widely accepted gene-specific and cross-gene family benchmarks and demonstrate that our method outperforms other state-of-the-art algorithms for predicting the interaction of new chemicals with multiple proteins. Thus, the proposed algorithm may provide a powerful tool for multi-target drug design. PMID:27958331

Improved genome-scale multi-target virtual screening via a novel collaborative filtering approach to cold-start problem.

PubMed

Lim, Hansaim; Gray, Paul; Xie, Lei; Poleksic, Aleksandar

2016-12-13

Conventional one-drug-one-gene approach has been of limited success in modern drug discovery. Polypharmacology, which focuses on searching for multi-targeted drugs to perturb disease-causing networks instead of designing selective ligands to target individual proteins, has emerged as a new drug discovery paradigm. Although many methods for single-target virtual screening have been developed to improve the efficiency of drug discovery, few of these algorithms are designed for polypharmacology. Here, we present a novel theoretical framework and a corresponding algorithm for genome-scale multi-target virtual screening based on the one-class collaborative filtering technique. Our method overcomes the sparseness of the protein-chemical interaction data by means of interaction matrix weighting and dual regularization from both chemicals and proteins. While the statistical foundation behind our method is general enough to encompass genome-wide drug off-target prediction, the program is specifically tailored to find protein targets for new chemicals with little to no available interaction data. We extensively evaluate our method using a number of the most widely accepted gene-specific and cross-gene family benchmarks and demonstrate that our method outperforms other state-of-the-art algorithms for predicting the interaction of new chemicals with multiple proteins. Thus, the proposed algorithm may provide a powerful tool for multi-target drug design.

A rational workflow for sequential virtual screening of chemical libraries on searching for new tyrosinase inhibitors.

PubMed

Le-Thi-Thu, Huong; Casanola-Martín, Gerardo M; Marrero-Ponce, Yovani; Rescigno, Antonio; Abad, Concepcion; Khan, Mahmud Tareq Hassan

2014-01-01

The tyrosinase is a bifunctional, copper-containing enzyme widely distributed in the phylogenetic tree. This enzyme is involved in the production of melanin and some other pigments in humans, animals and plants, including skin pigmentations in mammals, and browning process in plants and vegetables. Therefore, enzyme inhibitors has been under the attention of the scientist community, due to its broad applications in food, cosmetic, agricultural and medicinal fields, to avoid the undesirable effects of abnormal melanin overproduction. However, the research of novel chemical with antityrosinase activity demands the use of more efficient tools to speed up the tyrosinase inhibitors discovery process. This chapter is focused in the different components of a predictive modeling workflow for the identification and prioritization of potential new compounds with activity against the tyrosinase enzyme. In this case, two structure chemical libraries Spectrum Collection and Drugbank are used in this attempt to combine different virtual screening data mining techniques, in a sequential manner helping to avoid the usually expensive and time consuming traditional methods. Some of the sequential steps summarize here comprise the use of drug-likeness filters, similarity searching, classification and potency QSAR multiclassifier systems, modeling molecular interactions systems, and similarity/diversity analysis. Finally, the methodologies showed here provide a rational workflow for virtual screening hit analysis and selection as a promissory drug discovery strategy for use in target identification phase.

NALDB: nucleic acid ligand database for small molecules targeting nucleic acid

PubMed Central

Kumar Mishra, Subodh; Kumar, Amit

2016-01-01

Nucleic acid ligand database (NALDB) is a unique database that provides detailed information about the experimental data of small molecules that were reported to target several types of nucleic acid structures. NALDB is the first ligand database that contains ligand information for all type of nucleic acid. NALDB contains more than 3500 ligand entries with detailed pharmacokinetic and pharmacodynamic information such as target name, target sequence, ligand 2D/3D structure, SMILES, molecular formula, molecular weight, net-formal charge, AlogP, number of rings, number of hydrogen bond donor and acceptor, potential energy along with their Ki, Kd, IC50 values. All these details at single platform would be helpful for the development and betterment of novel ligands targeting nucleic acids that could serve as a potential target in different diseases including cancers and neurological disorders. With maximum 255 conformers for each ligand entry, our database is a multi-conformer database and can facilitate the virtual screening process. NALDB provides powerful web-based search tools that make database searching efficient and simplified using option for text as well as for structure query. NALDB also provides multi-dimensional advanced search tool which can screen the database molecules on the basis of molecular properties of ligand provided by database users. A 3D structure visualization tool has also been included for 3D structure representation of ligands. NALDB offers an inclusive pharmacological information and the structurally flexible set of small molecules with their three-dimensional conformers that can accelerate the virtual screening and other modeling processes and eventually complement the nucleic acid-based drug discovery research. NALDB can be routinely updated and freely available on bsbe.iiti.ac.in/bsbe/naldb/HOME.php. Database URL: http://bsbe.iiti.ac.in/bsbe/naldb/HOME.php PMID:26896846

Novel Hybrid Virtual Screening Protocol Based on Molecular Docking and Structure-Based Pharmacophore for Discovery of Methionyl-tRNA Synthetase Inhibitors as Antibacterial Agents

PubMed Central

Liu, Chi; He, Gu; Jiang, Qinglin; Han, Bo; Peng, Cheng

2013-01-01

Methione tRNA synthetase (MetRS) is an essential enzyme involved in protein biosynthesis in all living organisms and is a potential antibacterial target. In the current study, the structure-based pharmacophore (SBP)-guided method has been suggested to generate a comprehensive pharmacophore of MetRS based on fourteen crystal structures of MetRS-inhibitor complexes. In this investigation, a hybrid protocol of a virtual screening method, comprised of pharmacophore model-based virtual screening (PBVS), rigid and flexible docking-based virtual screenings (DBVS), is used for retrieving new MetRS inhibitors from commercially available chemical databases. This hybrid virtual screening approach was then applied to screen the Specs (202,408 compounds) database, a structurally diverse chemical database. Fifteen hit compounds were selected from the final hits and shifted to experimental studies. These results may provide important information for further research of novel MetRS inhibitors as antibacterial agents. PMID:23839093

Impact of a virtual reality-based intervention on motor performance and balance of a child with cerebral palsy: a case study

PubMed Central

Pavão, Silvia Leticia; Arnoni, Joice Luiza Bruno; de Oliveira, Alyne Kalyane Câmara; Rocha, Nelci Adriana Cicuto Ferreira

2014-01-01

OBJECTIVE: To verify the effect of an intervention protocol using virtual reality (VR) on the motor performance and balance of a child with cerebral palsy (CP). CASE DESCRIPTION: To comply with the proposed objectives, a 7-year old child with spastic hemiplegic cerebral palsy (CP), GMFCS level I, was submitted to a physiotherapy intervention protocol of 12 45-minute sessions, twice a week, using virtual reality-based therapy. The protocol used a commercially-available console (XBOX(r)360 Kinect(r)) able to track and reproduce body movements on a screen. Prior to the intervention protocol, the child was evaluated using the Motor Development Scale (MDS) and the Pediatric Balance Scale (PBS) in order to assess motor development and balance, respectively. Two baseline assessments with a 2-week interval between each other were carried out for each tool. Then, the child was re-evaluated after the twelfth session. The results showed no changes in the two baseline scores. After the intervention protocol, the child improved his scores in both tools used: the PBS score increased by 3 points, reaching the maximal score, and the MDS increased from a much inferior motor performance to just an inferior motor performance. COMMENTS: The evidence presented in this case supports the use of virtual reality as a promising tool to be incorporated into the rehabilitation process of patients with neuromotor dysfunction. PMID:25511004

An investigation of the efficacy of collaborative virtual reality systems for moderated remote usability testing.

PubMed

Chalil Madathil, Kapil; Greenstein, Joel S

2017-11-01

Collaborative virtual reality-based systems have integrated high fidelity voice-based communication, immersive audio and screen-sharing tools into virtual environments. Such three-dimensional collaborative virtual environments can mirror the collaboration among usability test participants and facilitators when they are physically collocated, potentially enabling moderated usability tests to be conducted effectively when the facilitator and participant are located in different places. We developed a virtual collaborative three-dimensional remote moderated usability testing laboratory and employed it in a controlled study to evaluate the effectiveness of moderated usability testing in a collaborative virtual reality-based environment with two other moderated usability testing methods: the traditional lab approach and Cisco WebEx, a web-based conferencing and screen sharing approach. Using a mixed methods experimental design, 36 test participants and 12 test facilitators were asked to complete representative tasks on a simulated online shopping website. The dependent variables included the time taken to complete the tasks; the usability defects identified and their severity; and the subjective ratings on the workload index, presence and satisfaction questionnaires. Remote moderated usability testing methodology using a collaborative virtual reality system performed similarly in terms of the total number of defects identified, the number of high severity defects identified and the time taken to complete the tasks with the other two methodologies. The overall workload experienced by the test participants and facilitators was the least with the traditional lab condition. No significant differences were identified for the workload experienced with the virtual reality and the WebEx conditions. However, test participants experienced greater involvement and a more immersive experience in the virtual environment than in the WebEx condition. The ratings for the virtual environment condition were not significantly different from those for the traditional lab condition. The results of this study suggest that participants were productive and enjoyed the virtual lab condition, indicating the potential of a virtual world based approach as an alternative to conventional approaches for synchronous usability testing. Copyright © 2017 Elsevier Ltd. All rights reserved.

Virtual screening of compound libraries.

PubMed

Cerqueira, Nuno M F S A; Sousa, Sérgio F; Fernandes, Pedro A; Ramos, Maria João

2009-01-01

During the last decade, Virtual Screening (VS) has definitively established itself as an important part of the drug discovery and development process. VS involves the selection of likely drug candidates from large libraries of chemical structures by using computational methodologies, but the generic definition of VS encompasses many different methodologies. This chapter provides an introduction to the field by reviewing a variety of important aspects, including the different types of virtual screening methods, and the several steps required for a successful virtual screening campaign within a state-of-the-art approach, from target selection to postfilter application. This analysis is further complemented with a small collection important VS success stories.

Protein tyrosine phosphatases: Ligand interaction analysis and optimisation of virtual screening.

PubMed

Ghattas, Mohammad A; Atatreh, Noor; Bichenkova, Elena V; Bryce, Richard A

2014-07-01

Docking-based virtual screening is an established component of structure-based drug discovery. Nevertheless, scoring and ranking of computationally docked ligand libraries still suffer from many false positives. Identifying optimal docking parameters for a target protein prior to virtual screening can improve experimental hit rates. Here, we examine protocols for virtual screening against the important but challenging class of drug target, protein tyrosine phosphatases. In this study, common interaction features were identified from analysis of protein-ligand binding geometries of more than 50 complexed phosphatase crystal structures. It was found that two interactions were consistently formed across all phosphatase inhibitors: (1) a polar contact with the conserved arginine residue, and (2) at least one interaction with the P-loop backbone amide. In order to investigate the significance of these features on phosphatase-ligand binding, a series of seeded virtual screening experiments were conducted on three phosphatase enzymes, PTP1B, Cdc25b and IF2. It was observed that when the conserved arginine and P-loop amide interactions were used as pharmacophoric constraints during docking, enrichment of the virtual screen significantly increased in the three studied phosphatases, by up to a factor of two in some cases. Additionally, the use of such pharmacophoric constraints considerably improved the ability of docking to predict the inhibitor's bound pose, decreasing RMSD to the crystallographic geometry by 43% on average. Constrained docking improved enrichment of screens against both open and closed conformations of PTP1B. Incorporation of an ordered water molecule in PTP1B screening was also found to generally improve enrichment. The knowledge-based computational strategies explored here can potentially inform structure-based design of new phosphatase inhibitors using docking-based virtual screening. Copyright © 2014 Elsevier Inc. All rights reserved.

Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification

PubMed Central

Ballester, Pedro J.; Mangold, Martina; Howard, Nigel I.; Robinson, Richard L. Marchese; Abell, Chris; Blumberger, Jochen; Mitchell, John B. O.

2012-01-01

One of the initial steps of modern drug discovery is the identification of small organic molecules able to inhibit a target macromolecule of therapeutic interest. A small proportion of these hits are further developed into lead compounds, which in turn may ultimately lead to a marketed drug. A commonly used screening protocol used for this task is high-throughput screening (HTS). However, the performance of HTS against antibacterial targets has generally been unsatisfactory, with high costs and low rates of hit identification. Here, we present a novel computational methodology that is able to identify a high proportion of structurally diverse inhibitors by searching unusually large molecular databases in a time-, cost- and resource-efficient manner. This virtual screening methodology was tested prospectively on two versions of an antibacterial target (type II dehydroquinase from Mycobacterium tuberculosis and Streptomyces coelicolor), for which HTS has not provided satisfactory results and consequently practically all known inhibitors are derivatives of the same core scaffold. Overall, our protocols identified 100 new inhibitors, with calculated Ki ranging from 4 to 250 μM (confirmed hit rates are 60% and 62% against each version of the target). Most importantly, over 50 new active molecular scaffolds were discovered that underscore the benefits that a wide application of prospectively validated in silico screening tools is likely to bring to antibacterial hit identification. PMID:22933186

Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification.

PubMed

Ballester, Pedro J; Mangold, Martina; Howard, Nigel I; Robinson, Richard L Marchese; Abell, Chris; Blumberger, Jochen; Mitchell, John B O

2012-12-07

One of the initial steps of modern drug discovery is the identification of small organic molecules able to inhibit a target macromolecule of therapeutic interest. A small proportion of these hits are further developed into lead compounds, which in turn may ultimately lead to a marketed drug. A commonly used screening protocol used for this task is high-throughput screening (HTS). However, the performance of HTS against antibacterial targets has generally been unsatisfactory, with high costs and low rates of hit identification. Here, we present a novel computational methodology that is able to identify a high proportion of structurally diverse inhibitors by searching unusually large molecular databases in a time-, cost- and resource-efficient manner. This virtual screening methodology was tested prospectively on two versions of an antibacterial target (type II dehydroquinase from Mycobacterium tuberculosis and Streptomyces coelicolor), for which HTS has not provided satisfactory results and consequently practically all known inhibitors are derivatives of the same core scaffold. Overall, our protocols identified 100 new inhibitors, with calculated K(i) ranging from 4 to 250 μM (confirmed hit rates are 60% and 62% against each version of the target). Most importantly, over 50 new active molecular scaffolds were discovered that underscore the benefits that a wide application of prospectively validated in silico screening tools is likely to bring to antibacterial hit identification.

Adapting Document Similarity Measures for Ligand-Based Virtual Screening.

PubMed

Himmat, Mubarak; Salim, Naomie; Al-Dabbagh, Mohammed Mumtaz; Saeed, Faisal; Ahmed, Ali

2016-04-13

Quantifying the similarity of molecules is considered one of the major tasks in virtual screening. There are many similarity measures that have been proposed for this purpose, some of which have been derived from document and text retrieving areas as most often these similarity methods give good results in document retrieval and can achieve good results in virtual screening. In this work, we propose a similarity measure for ligand-based virtual screening, which has been derived from a text processing similarity measure. It has been adopted to be suitable for virtual screening; we called this proposed measure the Adapted Similarity Measure of Text Processing (ASMTP). For evaluating and testing the proposed ASMTP we conducted several experiments on two different benchmark datasets: the Maximum Unbiased Validation (MUV) and the MDL Drug Data Report (MDDR). The experiments have been conducted by choosing 10 reference structures from each class randomly as queries and evaluate them in the recall of cut-offs at 1% and 5%. The overall obtained results are compared with some similarity methods including the Tanimoto coefficient, which are considered to be the conventional and standard similarity coefficients for fingerprint-based similarity calculations. The achieved results show that the performance of ligand-based virtual screening is better and outperforms the Tanimoto coefficients and other methods.

Evaluating the Predictivity of Virtual Screening for Abl Kinase Inhibitors to Hinder Drug Resistance

PubMed Central

Gani, Osman A B S M; Narayanan, Dilip; Engh, Richard A

2013-01-01

Virtual screening methods are now widely used in early stages of drug discovery, aiming to rank potential inhibitors. However, any practical ligand set (of active or inactive compounds) chosen for deriving new virtual screening approaches cannot fully represent all relevant chemical space for potential new compounds. In this study, we have taken a retrospective approach to evaluate virtual screening methods for the leukemia target kinase ABL1 and its drug-resistant mutant ABL1-T315I. ‘Dual active’ inhibitors against both targets were grouped together with inactive ligands chosen from different decoy sets and tested with virtual screening approaches with and without explicit use of target structures (docking). We show how various scoring functions and choice of inactive ligand sets influence overall and early enrichment of the libraries. Although ligand-based methods, for example principal component analyses of chemical properties, can distinguish some decoy sets from active compounds, the addition of target structural information via docking improves enrichment, and explicit consideration of multiple target conformations (i.e. types I and II) achieves best enrichment of active versus inactive ligands, even without assuming knowledge of the binding mode. We believe that this study can be extended to other therapeutically important kinases in prospective virtual screening studies. PMID:23746052

DockingApp: a user friendly interface for facilitated docking simulations with AutoDock Vina.

PubMed

Di Muzio, Elena; Toti, Daniele; Polticelli, Fabio

2017-02-01

Molecular docking is a powerful technique that helps uncover the structural and energetic bases of the interaction between macromolecules and substrates, endogenous and exogenous ligands, and inhibitors. Moreover, this technique plays a pivotal role in accelerating the screening of large libraries of compounds for drug development purposes. The need to promote community-driven drug development efforts, especially as far as neglected diseases are concerned, calls for user-friendly tools to allow non-expert users to exploit the full potential of molecular docking. Along this path, here is described the implementation of DockingApp, a freely available, extremely user-friendly, platform-independent application for performing docking simulations and virtual screening tasks using AutoDock Vina. DockingApp sports an intuitive graphical user interface which greatly facilitates both the input phase and the analysis of the results, which can be visualized in graphical form using the embedded JMol applet. The application comes with the DrugBank set of more than 1400 ready-to-dock, FDA-approved drugs, to facilitate virtual screening and drug repurposing initiatives. Furthermore, other databases of compounds such as ZINC, available also in AutoDock format, can be readily and easily plugged in.

A Stochastic Spiking Neural Network for Virtual Screening.

PubMed

Morro, A; Canals, V; Oliver, A; Alomar, M L; Galan-Prado, F; Ballester, P J; Rossello, J L

2018-04-01

Virtual screening (VS) has become a key computational tool in early drug design and screening performance is of high relevance due to the large volume of data that must be processed to identify molecules with the sought activity-related pattern. At the same time, the hardware implementations of spiking neural networks (SNNs) arise as an emerging computing technique that can be applied to parallelize processes that normally present a high cost in terms of computing time and power. Consequently, SNN represents an attractive alternative to perform time-consuming processing tasks, such as VS. In this brief, we present a smart stochastic spiking neural architecture that implements the ultrafast shape recognition (USR) algorithm achieving two order of magnitude of speed improvement with respect to USR software implementations. The neural system is implemented in hardware using field-programmable gate arrays allowing a highly parallelized USR implementation. The results show that, due to the high parallelization of the system, millions of compounds can be checked in reasonable times. From these results, we can state that the proposed architecture arises as a feasible methodology to efficiently enhance time-consuming data-mining processes such as 3-D molecular similarity search.

DockingApp: a user friendly interface for facilitated docking simulations with AutoDock Vina

NASA Astrophysics Data System (ADS)

Di Muzio, Elena; Toti, Daniele; Polticelli, Fabio

2017-02-01

Molecular docking is a powerful technique that helps uncover the structural and energetic bases of the interaction between macromolecules and substrates, endogenous and exogenous ligands, and inhibitors. Moreover, this technique plays a pivotal role in accelerating the screening of large libraries of compounds for drug development purposes. The need to promote community-driven drug development efforts, especially as far as neglected diseases are concerned, calls for user-friendly tools to allow non-expert users to exploit the full potential of molecular docking. Along this path, here is described the implementation of DockingApp, a freely available, extremely user-friendly, platform-independent application for performing docking simulations and virtual screening tasks using AutoDock Vina. DockingApp sports an intuitive graphical user interface which greatly facilitates both the input phase and the analysis of the results, which can be visualized in graphical form using the embedded JMol applet. The application comes with the DrugBank set of more than 1400 ready-to-dock, FDA-approved drugs, to facilitate virtual screening and drug repurposing initiatives. Furthermore, other databases of compounds such as ZINC, available also in AutoDock format, can be readily and easily plugged in.

DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites.

PubMed

Gowthaman, Ragul; Miller, Sven A; Rogers, Steven; Khowsathit, Jittasak; Lan, Lan; Bai, Nan; Johnson, David K; Liu, Chunjing; Xu, Liang; Anbanandam, Asokan; Aubé, Jeffrey; Roy, Anuradha; Karanicolas, John

2016-05-12

Protein-protein interactions represent an exciting and challenging target class for therapeutic intervention using small molecules. Protein interaction sites are often devoid of the deep surface pockets presented by "traditional" drug targets, and crystal structures reveal that inhibitors typically engage these sites using very shallow binding modes. As a consequence, modern virtual screening tools developed to identify inhibitors of traditional drug targets do not perform as well when they are instead deployed at protein interaction sites. To address the need for novel inhibitors of important protein interactions, here we introduce an alternate docking strategy specifically designed for this regime. Our method, termed DARC (Docking Approach using Ray-Casting), matches the topography of a surface pocket "observed" from within the protein to the topography "observed" when viewing a potential ligand from the same vantage point. We applied DARC to carry out a virtual screen against the protein interaction site of human antiapoptotic protein Mcl-1 and found that four of the top-scoring 21 compounds showed clear inhibition in a biochemical assay. The Ki values for these compounds ranged from 1.2 to 21 μM, and each had ligand efficiency comparable to promising small-molecule inhibitors of other protein-protein interactions. These hit compounds do not resemble the natural (protein) binding partner of Mcl-1, nor do they resemble any known inhibitors of Mcl-1. Our results thus demonstrate the utility of DARC for identifying novel inhibitors of protein-protein interactions.

Performance of machine-learning scoring functions in structure-based virtual screening

PubMed Central

Wójcikowski, Maciej; Ballester, Pedro J.; Siedlecki, Pawel

2017-01-01

Classical scoring functions have reached a plateau in their performance in virtual screening and binding affinity prediction. Recently, machine-learning scoring functions trained on protein-ligand complexes have shown great promise in small tailored studies. They have also raised controversy, specifically concerning model overfitting and applicability to novel targets. Here we provide a new ready-to-use scoring function (RF-Score-VS) trained on 15 426 active and 893 897 inactive molecules docked to a set of 102 targets. We use the full DUD-E data sets along with three docking tools, five classical and three machine-learning scoring functions for model building and performance assessment. Our results show RF-Score-VS can substantially improve virtual screening performance: RF-Score-VS top 1% provides 55.6% hit rate, whereas that of Vina only 16.2% (for smaller percent the difference is even more encouraging: RF-Score-VS top 0.1% achieves 88.6% hit rate for 27.5% using Vina). In addition, RF-Score-VS provides much better prediction of measured binding affinity than Vina (Pearson correlation of 0.56 and −0.18, respectively). Lastly, we test RF-Score-VS on an independent test set from the DEKOIS benchmark and observed comparable results. We provide full data sets to facilitate further research in this area (http://github.com/oddt/rfscorevs) as well as ready-to-use RF-Score-VS (http://github.com/oddt/rfscorevs_binary). PMID:28440302

Computational methods in drug discovery

PubMed Central

Leelananda, Sumudu P

2016-01-01

The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery projects. Additionally, increasing knowledge of biological structures, as well as increasing computer power have made it possible to use computational methods effectively in various phases of the drug discovery and development pipeline. The importance of in silico tools is greater than ever before and has advanced pharmaceutical research. Here we present an overview of computational methods used in different facets of drug discovery and highlight some of the recent successes. In this review, both structure-based and ligand-based drug discovery methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein–ligand docking, pharmacophore modeling and QSAR techniques are reviewed. PMID:28144341

Computational methods in drug discovery.

PubMed

Leelananda, Sumudu P; Lindert, Steffen

2016-01-01

The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery projects. Additionally, increasing knowledge of biological structures, as well as increasing computer power have made it possible to use computational methods effectively in various phases of the drug discovery and development pipeline. The importance of in silico tools is greater than ever before and has advanced pharmaceutical research. Here we present an overview of computational methods used in different facets of drug discovery and highlight some of the recent successes. In this review, both structure-based and ligand-based drug discovery methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein-ligand docking, pharmacophore modeling and QSAR techniques are reviewed.

Virtual Colonoscopy Screening With Ultra Low-Dose CT and Less-Stressful Bowel Preparation: A Computer Simulation Study

NASA Astrophysics Data System (ADS)

Wang, Jing; Wang, Su; Li, Lihong; Fan, Yi; Lu, Hongbing; Liang, Zhengrong

2008-10-01

Computed tomography colonography (CTC) or CT-based virtual colonoscopy (VC) is an emerging tool for detection of colonic polyps. Compared to the conventional fiber-optic colonoscopy, VC has demonstrated the potential to become a mass screening modality in terms of safety, cost, and patient compliance. However, current CTC delivers excessive X-ray radiation to the patient during data acquisition. The radiation is a major concern for screening application of CTC. In this work, we performed a simulation study to demonstrate a possible ultra low-dose CT technique for VC. The ultra low-dose abdominal CT images were simulated by adding noise to the sinograms of the patient CTC images acquired with normal dose scans at 100 mA s levels. The simulated noisy sinogram or projection data were first processed by a Karhunen-Loeve domain penalized weighted least-squares (KL-PWLS) restoration method and then reconstructed by a filtered backprojection algorithm for the ultra low-dose CT images. The patient-specific virtual colon lumen was constructed and navigated by a VC system after electronic colon cleansing of the orally-tagged residue stool and fluid. By the KL-PWLS noise reduction, the colon lumen can successfully be constructed and the colonic polyp can be detected in an ultra low-dose level below 50 mA s. Polyp detection can be found more easily by the KL-PWLS noise reduction compared to the results using the conventional noise filters, such as Hanning filter. These promising results indicate the feasibility of an ultra low-dose CTC pipeline for colon screening with less-stressful bowel preparation by fecal tagging with oral contrast.

Tandem application of ligand-based virtual screening and G4-OAS assay to identify novel G-quadruplex-targeting chemotypes.

PubMed

Musumeci, Domenica; Amato, Jussara; Zizza, Pasquale; Platella, Chiara; Cosconati, Sandro; Cingolani, Chiara; Biroccio, Annamaria; Novellino, Ettore; Randazzo, Antonio; Giancola, Concetta; Pagano, Bruno; Montesarchio, Daniela

2017-05-01

G-quadruplex (G4) structures are key elements in the regulation of cancer cell proliferation and their targeting is deemed to be a promising strategy in anticancer therapy. A tandem application of ligand-based virtual screening (VS) calculations together with the experimental G-quadruplex on Oligo Affinity Support (G4-OAS) assay was employed to discover novel G4-targeting compounds. The interaction of the selected compounds with the investigated G4 in solution was analysed through a series of biophysical techniques and their biological activity investigated by immunofluorescence and MTT assays. A focused library of 60 small molecules, designed as putative G4 groove binders, was identified through the VS. The G4-OAS experimental screening led to the selection of 7 ligands effectively interacting with the G4-forming human telomeric DNA. Evaluation of the biological activity of the selected compounds showed that 3 ligands of this sub-library induced a marked telomere-localized DNA damage response in human tumour cells. The combined application of virtual and experimental screening tools proved to be a successful strategy to identify new bioactive chemotypes able to target the telomeric G4 DNA. These compounds may represent useful leads for the development of more potent and selective G4 ligands. Expanding the repertoire of the available G4-targeting chemotypes with improved physico-chemical features, in particular aiming at the discovery of novel, selective G4 telomeric ligands, can help in developing effective anti-cancer drugs with fewer side effects. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. Copyright © 2017 Elsevier B.V. All rights reserved.

VEVI: A Virtual Reality Tool For Robotic Planetary Explorations

NASA Technical Reports Server (NTRS)

Piguet, Laurent; Fong, Terry; Hine, Butler; Hontalas, Phil; Nygren, Erik

1994-01-01

The Virtual Environment Vehicle Interface (VEVI), developed by the NASA Ames Research Center's Intelligent Mechanisms Group, is a modular operator interface for direct teleoperation and supervisory control of robotic vehicles. Virtual environments enable the efficient display and visualization of complex data. This characteristic allows operators to perceive and control complex systems in a natural fashion, utilizing the highly-evolved human sensory system. VEVI utilizes real-time, interactive, 3D graphics and position / orientation sensors to produce a range of interface modalities from the flat panel (windowed or stereoscopic) screen displays to head mounted/head-tracking stereo displays. The interface provides generic video control capability and has been used to control wheeled, legged, air bearing, and underwater vehicles in a variety of different environments. VEVI was designed and implemented to be modular, distributed and easily operated through long-distance communication links, using a communication paradigm called SYNERGY.

Designing a Pediatric Severe Sepsis Screening Tool

PubMed Central

Sepanski, Robert J.; Godambe, Sandip A.; Mangum, Christopher D.; Bovat, Christine S.; Zaritsky, Arno L.; Shah, Samir H.

2014-01-01

We sought to create a screening tool with improved predictive value for pediatric severe sepsis (SS) and septic shock that can be incorporated into the electronic medical record and actively screen all patients arriving at a pediatric emergency department (ED). “Gold standard” SS cases were identified using a combination of coded discharge diagnosis and physician chart review from 7,402 children who visited a pediatric ED over 2 months. The tool’s identification of SS was initially based on International Consensus Conference on Pediatric Sepsis (ICCPS) parameters that were refined by an iterative, virtual process that allowed us to propose successive changes in sepsis detection parameters in order to optimize the tool’s predictive value based on receiver operating characteristics (ROC). Age-specific normal and abnormal values for heart rate (HR) and respiratory rate (RR) were empirically derived from 143,603 children seen in a second pediatric ED over 3 years. Univariate analyses were performed for each measure in the tool to assess its association with SS and to characterize it as an “early” or “late” indicator of SS. A split-sample was used to validate the final, optimized tool. The final tool incorporated age-specific thresholds for abnormal HR and RR and employed a linear temperature correction for each category. The final tool’s positive predictive value was 48.7%, a significant, nearly threefold improvement over the original ICCPS tool. False positive systemic inflammatory response syndrome identifications were nearly sixfold lower. PMID:24982852

An Integrated In Silico Method to Discover Novel Rock1 Inhibitors: Multi- Complex-Based Pharmacophore, Molecular Dynamics Simulation and Hybrid Protocol Virtual Screening.

PubMed

Chen, Haining; Li, Sijia; Hu, Yajiao; Chen, Guo; Jiang, Qinglin; Tong, Rongsheng; Zang, Zhihe; Cai, Lulu

2016-01-01

Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) is an important regulator of focal adhesion, actomyosin contraction and cell motility. In this manuscript, a combination of the multi-complex-based pharmacophore (MCBP), molecular dynamics simulation and a hybrid protocol of a virtual screening method, comprised of multipharmacophore- based virtual screening (PBVS) and ensemble docking-based virtual screening (DBVS) methods were used for retrieving novel ROCK1 inhibitors from the natural products database embedded in the ZINC database. Ten hit compounds were selected from the hit compounds, and five compounds were tested experimentally. Thus, these results may provide valuable information for further discovery of more novel ROCK1 inhibitors.

Virtual Manufacturing Techniques Designed and Applied to Manufacturing Activities in the Manufacturing Integration and Technology Branch

NASA Technical Reports Server (NTRS)

Shearrow, Charles A.

1999-01-01

One of the identified goals of EM3 is to implement virtual manufacturing by the time the year 2000 has ended. To realize this goal of a true virtual manufacturing enterprise the initial development of a machinability database and the infrastructure must be completed. This will consist of the containment of the existing EM-NET problems and developing machine, tooling, and common materials databases. To integrate the virtual manufacturing enterprise with normal day to day operations the development of a parallel virtual manufacturing machinability database, virtual manufacturing database, virtual manufacturing paradigm, implementation/integration procedure, and testable verification models must be constructed. Common and virtual machinability databases will include the four distinct areas of machine tools, available tooling, common machine tool loads, and a materials database. The machine tools database will include the machine envelope, special machine attachments, tooling capacity, location within NASA-JSC or with a contractor, and availability/scheduling. The tooling database will include available standard tooling, custom in-house tooling, tool properties, and availability. The common materials database will include materials thickness ranges, strengths, types, and their availability. The virtual manufacturing databases will consist of virtual machines and virtual tooling directly related to the common and machinability databases. The items to be completed are the design and construction of the machinability databases, virtual manufacturing paradigm for NASA-JSC, implementation timeline, VNC model of one bridge mill and troubleshoot existing software and hardware problems with EN4NET. The final step of this virtual manufacturing project will be to integrate other production sites into the databases bringing JSC's EM3 into a position of becoming a clearing house for NASA's digital manufacturing needs creating a true virtual manufacturing enterprise.

Collaborative Workspaces within Distributed Virtual Environments.

DTIC Science & Technology

1996-12-01

such as a text document, a 3D model, or a captured image using a collaborative workspace called the InPerson Whiteboard . The Whiteboard contains a...commands for editing objects drawn on the screen. Finally, when the call is completed, the Whiteboard can be saved to a file for future use . IRIS Annotator... use , and a shared whiteboard that includes a number of multimedia annotation tools. Both systems are also mindful of bandwidth limitations and can

Creating and virtually screening databases of fluorescently-labelled compounds for the discovery of target-specific molecular probes

NASA Astrophysics Data System (ADS)

Kamstra, Rhiannon L.; Dadgar, Saedeh; Wigg, John; Chowdhury, Morshed A.; Phenix, Christopher P.; Floriano, Wely B.

2014-11-01

Our group has recently demonstrated that virtual screening is a useful technique for the identification of target-specific molecular probes. In this paper, we discuss some of our proof-of-concept results involving two biologically relevant target proteins, and report the development of a computational script to generate large databases of fluorescence-labelled compounds for computer-assisted molecular design. The virtual screening of a small library of 1,153 fluorescently-labelled compounds against two targets, and the experimental testing of selected hits reveal that this approach is efficient at identifying molecular probes, and that the screening of a labelled library is preferred over the screening of base compounds followed by conjugation of confirmed hits. The automated script for library generation explores the known reactivity of commercially available dyes, such as NHS-esters, to create large virtual databases of fluorescence-tagged small molecules that can be easily synthesized in a laboratory. A database of 14,862 compounds, each tagged with the ATTO680 fluorophore was generated with the automated script reported here. This library is available for downloading and it is suitable for virtual ligand screening aiming at the identification of target-specific fluorescent molecular probes.

Spherical harmonics coefficients for ligand-based virtual screening of cyclooxygenase inhibitors.

PubMed

Wang, Quan; Birod, Kerstin; Angioni, Carlo; Grösch, Sabine; Geppert, Tim; Schneider, Petra; Rupp, Matthias; Schneider, Gisbert

2011-01-01

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.

Inhibitors of Helicobacter pylori Protease HtrA Found by ‘Virtual Ligand’ Screening Combat Bacterial Invasion of Epithelia

PubMed Central

Schneider, Petra; Hoy, Benjamin; Wessler, Silja; Schneider, Gisbert

2011-01-01

Background The human pathogen Helicobacter pylori (H. pylori) is a main cause for gastric inflammation and cancer. Increasing bacterial resistance against antibiotics demands for innovative strategies for therapeutic intervention. Methodology/Principal Findings We present a method for structure-based virtual screening that is based on the comprehensive prediction of ligand binding sites on a protein model and automated construction of a ligand-receptor interaction map. Pharmacophoric features of the map are clustered and transformed in a correlation vector (‘virtual ligand’) for rapid virtual screening of compound databases. This computer-based technique was validated for 18 different targets of pharmaceutical interest in a retrospective screening experiment. Prospective screening for inhibitory agents was performed for the protease HtrA from the human pathogen H. pylori using a homology model of the target protein. Among 22 tested compounds six block E-cadherin cleavage by HtrA in vitro and result in reduced scattering and wound healing of gastric epithelial cells, thereby preventing bacterial infiltration of the epithelium. Conclusions/Significance This study demonstrates that receptor-based virtual screening with a permissive (‘fuzzy’) pharmacophore model can help identify small bioactive agents for combating bacterial infection. PMID:21483848

Scaffold-Focused Virtual Screening: Prospective Application to the Discovery of TTK Inhibitors

PubMed Central

2013-01-01

We describe and apply a scaffold-focused virtual screen based upon scaffold trees to the mitotic kinase TTK (MPS1). Using level 1 of the scaffold tree, we perform both 2D and 3D similarity searches between a query scaffold and a level 1 scaffold library derived from a 2 million compound library; 98 compounds from 27 unique top-ranked level 1 scaffolds are selected for biochemical screening. We show that this scaffold-focused virtual screen prospectively identifies eight confirmed active compounds that are structurally differentiated from the query compound. In comparison, 100 compounds were selected for biochemical screening using a virtual screen based upon whole molecule similarity resulting in 12 confirmed active compounds that are structurally similar to the query compound. We elucidated the binding mode for four of the eight confirmed scaffold hops to TTK by determining their protein–ligand crystal structures; each represents a ligand-efficient scaffold for inhibitor design. PMID:23672464

Evaluation of a novel Serious Game based assessment tool for patients with Alzheimer's disease.

PubMed

Vallejo, Vanessa; Wyss, Patric; Rampa, Luca; Mitache, Andrei V; Müri, René M; Mosimann, Urs P; Nef, Tobias

2017-01-01

Despite growing interest in developing ecological assessment of difficulties in patients with Alzheimer's disease new methods assessing the cognitive difficulties related to functional activities are missing. To complete current evaluation, the use of Serious Games can be a promising approach as it offers the possibility to recreate a virtual environment with daily living activities and a precise and complete cognitive evaluation. The aim of the present study was to evaluate the usability and the screening potential of a new ecological tool for assessment of cognitive functions in patients with Alzheimer's disease. Eighteen patients with Alzheimer's disease and twenty healthy controls participated to the study. They were asked to complete six daily living virtual tasks assessing several cognitive functions: three navigation tasks, one shopping task, one cooking task and one table preparation task following a one-day scenario. Usability of the game was evaluated through a questionnaire and through the analysis of the computer interactions for the two groups. Furthermore, the performances in terms of time to achieve the task and percentage of completion on the several tasks were recorded. Results indicate that both groups subjectively found the game user friendly and they were objectively able to play the game without computer interactions difficulties. Comparison of the performances between the two groups indicated a significant difference in terms of percentage of achievement of the several tasks and in terms of time they needed to achieve the several tasks. This study suggests that this new Serious Game based assessment tool is a user-friendly and ecological method to evaluate the cognitive abilities related to the difficulties patients can encounter in daily living activities and can be used as a screening tool as it allowed to distinguish Alzheimer's patient's performance from healthy controls.

Evaluation of the performance of 3D virtual screening protocols: RMSD comparisons, enrichment assessments, and decoy selection--what can we learn from earlier mistakes?

PubMed

Kirchmair, Johannes; Markt, Patrick; Distinto, Simona; Wolber, Gerhard; Langer, Thierry

2008-01-01

Within the last few years a considerable amount of evaluative studies has been published that investigate the performance of 3D virtual screening approaches. Thereby, in particular assessments of protein-ligand docking are facing remarkable interest in the scientific community. However, comparing virtual screening approaches is a non-trivial task. Several publications, especially in the field of molecular docking, suffer from shortcomings that are likely to affect the significance of the results considerably. These quality issues often arise from poor study design, biasing, by using improper or inexpressive enrichment descriptors, and from errors in interpretation of the data output. In this review we analyze recent literature evaluating 3D virtual screening methods, with focus on molecular docking. We highlight problematic issues and provide guidelines on how to improve the quality of computational studies. Since 3D virtual screening protocols are in general assessed by their ability to discriminate between active and inactive compounds, we summarize the impact of the composition and preparation of test sets on the outcome of evaluations. Moreover, we investigate the significance of both classic enrichment parameters and advanced descriptors for the performance of 3D virtual screening methods. Furthermore, we review the significance and suitability of RMSD as a measure for the accuracy of protein-ligand docking algorithms and of conformational space sub sampling algorithms.

When drug discovery meets web search: Learning to Rank for ligand-based virtual screening.

PubMed

Zhang, Wei; Ji, Lijuan; Chen, Yanan; Tang, Kailin; Wang, Haiping; Zhu, Ruixin; Jia, Wei; Cao, Zhiwei; Liu, Qi

2015-01-01

The rapid increase in the emergence of novel chemical substances presents a substantial demands for more sophisticated computational methodologies for drug discovery. In this study, the idea of Learning to Rank in web search was presented in drug virtual screening, which has the following unique capabilities of 1). Applicable of identifying compounds on novel targets when there is not enough training data available for these targets, and 2). Integration of heterogeneous data when compound affinities are measured in different platforms. A standard pipeline was designed to carry out Learning to Rank in virtual screening. Six Learning to Rank algorithms were investigated based on two public datasets collected from Binding Database and the newly-published Community Structure-Activity Resource benchmark dataset. The results have demonstrated that Learning to rank is an efficient computational strategy for drug virtual screening, particularly due to its novel use in cross-target virtual screening and heterogeneous data integration. To the best of our knowledge, we have introduced here the first application of Learning to Rank in virtual screening. The experiment workflow and algorithm assessment designed in this study will provide a standard protocol for other similar studies. All the datasets as well as the implementations of Learning to Rank algorithms are available at http://www.tongji.edu.cn/~qiliu/lor_vs.html. Graphical AbstractThe analogy between web search and ligand-based drug discovery.

ChemHTPS - A virtual high-throughput screening program suite for the chemical and materials sciences

NASA Astrophysics Data System (ADS)

Afzal, Mohammad Atif Faiz; Evangelista, William; Hachmann, Johannes

The discovery of new compounds, materials, and chemical reactions with exceptional properties is the key for the grand challenges in innovation, energy and sustainability. This process can be dramatically accelerated by means of the virtual high-throughput screening (HTPS) of large-scale candidate libraries. The resulting data can further be used to study the underlying structure-property relationships and thus facilitate rational design capability. This approach has been extensively used for many years in the drug discovery community. However, the lack of openly available virtual HTPS tools is limiting the use of these techniques in various other applications such as photovoltaics, optoelectronics, and catalysis. Thus, we developed ChemHTPS, a general-purpose, comprehensive and user-friendly suite, that will allow users to efficiently perform large in silico modeling studies and high-throughput analyses in these applications. ChemHTPS also includes a massively parallel molecular library generator which offers a multitude of options to customize and restrict the scope of the enumerated chemical space and thus tailor it for the demands of specific applications. To streamline the non-combinatorial exploration of chemical space, we incorporate genetic algorithms into the framework. In addition to implementing smarter algorithms, we also focus on the ease of use, workflow, and code integration to make this technology more accessible to the community.

Customizing G Protein-coupled receptor models for structure-based virtual screening.

PubMed

de Graaf, Chris; Rognan, Didier

2009-01-01

This review will focus on the construction, refinement, and validation of G Protein-coupled receptor models for the purpose of structure-based virtual screening. Practical tips and tricks derived from concrete modeling and virtual screening exercises to overcome the problems and pitfalls associated with the different steps of the receptor modeling workflow will be presented. These examples will not only include rhodopsin-like (class A), but also secretine-like (class B), and glutamate-like (class C) receptors. In addition, the review will present a careful comparative analysis of current crystal structures and their implication on homology modeling. The following themes will be discussed: i) the use of experimental anchors in guiding the modeling procedure; ii) amino acid sequence alignments; iii) ligand binding mode accommodation and binding cavity expansion; iv) proline-induced kinks in transmembrane helices; v) binding mode prediction and virtual screening by receptor-ligand interaction fingerprint scoring; vi) extracellular loop modeling; vii) virtual filtering schemes. Finally, an overview of several successful structure-based screening shows that receptor models, despite structural inaccuracies, can be efficiently used to find novel ligands.

Classification and virtual screening of androgen receptor antagonists.

PubMed

Li, Jiazhong; Gramatica, Paola

2010-05-24

Computational tools, such as quantitative structure-activity relationship (QSAR), are highly useful as screening support for prioritization of substances of very high concern (SVHC). From the practical point of view, QSAR models should be effective to pick out more active rather than inactive compounds, expressed as sensitivity in classification works. This research investigates the classification of a big data set of endocrine-disrupting chemicals (EDCs)-androgen receptor (AR) antagonists, mainly aiming to improve the external sensitivity and to screen for potential AR binders. The kNN, lazy IB1, and ADTree methods and the consensus approach were used to build different models, which improve the sensitivity on external chemicals from 57.1% (literature) to 76.4%. Additionally, the models' predictive abilities were further validated on a blind collected data set (sensitivity: 85.7%). Then the proposed classifiers were used: (i) to distinguish a set of AR binders into antagonists and agonists; (ii) to screen a combined estrogen receptor binder database to find out possible chemicals that can bind to both AR and ER; and (iii) to virtually screen our in-house environmental chemical database. The in silico screening results suggest: (i) that some compounds can affect the normal endocrine system through a complex mechanism binding both to ER and AR; (ii) new EDCs, which are nonER binders, but can in silico bind to AR, are recognized; and (iii) about 20% of compounds in a big data set of environmental chemicals are predicted as new AR antagonists. The priority should be given to them to experimentally test the binding activities with AR.

Virtual screening of a milk peptide database for the identification of food-derived antimicrobial peptides.

PubMed

Liu, Yufang; Eichler, Jutta; Pischetsrieder, Monika

2015-11-01

Milk provides a wide range of bioactive substances, such as antimicrobial peptides and proteins. Our study aimed to identify novel antimicrobial peptides naturally present in milk. The components of an endogenous bovine milk peptide database were virtually screened for charge, amphipathy, and predicted secondary structure. Thus, 23 of 248 screened peptides were identified as candidates for antimicrobial effects. After commercial synthesis, their antimicrobial activities were determined against Escherichia coli NEB5α, E. coli ATCC25922, and Bacillus subtilis ATCC6051. In the tested concentration range (<2 mM), bacteriostatic activity of 14 peptides was detected including nine peptides inhibiting both Gram-positive and Gram-negative bacteria. The most effective fragment was TKLTEEEKNRLNFLKKISQRYQKFΑLPQYLK corresponding to αS2 -casein151-181 , with minimum inhibitory concentration (MIC) of 4.0 μM against B. subtilis ATCC6051, and minimum inhibitory concentrations of 16.2 μM against both E. coli strains. Circular dichroism spectroscopy revealed conformational changes of most active peptides in a membrane-mimic environment, transitioning from an unordered to α-helical structure. Screening of food peptide databases by prediction tools is an efficient method to identify novel antimicrobial food-derived peptides. Milk-derived antimicrobial peptides may have potential use as functional food ingredients and help to understand the molecular mechanisms of anti-infective milk effects. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Stereo 3D vision adapter using commercial DIY goods

NASA Astrophysics Data System (ADS)

Sakamoto, Kunio; Ohara, Takashi

2009-10-01

The conventional display can show only one screen, but it is impossible to enlarge the size of a screen, for example twice. Meanwhile the mirror supplies us with the same image but this mirror image is usually upside down. Assume that the images on an original screen and a virtual screen in the mirror are completely different and both images can be displayed independently. It would be possible to enlarge a screen area twice. This extension method enables the observers to show the virtual image plane and to enlarge a screen area twice. Although the displaying region is doubled, this virtual display could not produce 3D images. In this paper, we present an extension method using a unidirectional diffusing image screen and an improvement for displaying a 3D image using orthogonal polarized image projection.

Experience with V-STORE: considerations on presence in virtual environments for effective neuropsychological rehabilitation of executive functions.

PubMed

Lo Priore, Corrado; Castelnuovo, Gianluca; Liccione, Diego; Liccione, Davide

2003-06-01

The paper discusses the use of immersive virtual reality systems for the cognitive rehabilitation of dysexecutive syndrome, usually caused by prefrontal brain injuries. With respect to classical P&P and flat-screen computer rehabilitative tools, IVR systems might prove capable of evoking a more intense and compelling sense of presence, thanks to the highly naturalistic subject-environment interaction allowed. Within a constructivist framework applied to holistic rehabilitation, we suggest that this difference might enhance the ecological validity of cognitive training, partly overcoming the implicit limits of a lab setting, which seem to affect non-immersive procedures especially when applied to dysexecutive symptoms. We tested presence in a pilot study applied to a new VR-based rehabilitation tool for executive functions, V-Store; it allows patients to explore a virtual environment where they solve six series of tasks, ordered for complexity and designed to stimulate executive functions, programming, categorical abstraction, short-term memory and attention. We compared sense of presence experienced by unskilled normal subjects, randomly assigned to immersive or non-immersive (flat screen) sessions of V-Store, through four different indexes: self-report questionnaire, psychophysiological (GSR, skin conductance), neuropsychological (incidental recall memory test related to auditory information coming from the "real" environment) and count of breaks in presence (BIPs). Preliminary results show in the immersive group a significantly higher GSR response during tasks; neuropsychological data (fewer recalled elements from "reality") and less BIPs only show a congruent but yet non-significant advantage for the immersive condition; no differences were evident from the self-report questionnaire. A larger experimental group is currently under examination to evaluate significance of these data, which also might prove interesting with respect to the question of objective-subjective measures of presence.

The Whole World In Your Hands: Using an Interactive Virtual Reality Sandbox for Geospatial Education and Outreach

NASA Astrophysics Data System (ADS)

Clucas, T.; Wirth, G. S.; Broderson, D.

2014-12-01

Traditional geospatial education tools such as maps and computer screens don't convey the rich topography present on Earth. Translating lines on a contour lines on a topo map to relief in a landscape can be a challenging concept to convey.A partnership between Alaska EPSCoR and the Geographic Information Network of Alaska has successfully constructed an Interactive Virtual Reality Sandbox, an education tool that in real-time projects and updates topographic contours on the surface of a sandbox. The sandbox has been successfully deployed at public science events as well as professional geospatial and geodesy conferences. Landscape change, precipitation, and evaporation can all be modeled, much to the delight of our enthusiasts, who range in age from 3 to 90. Visually, as well as haptically, demonstrating the effects of events (such as dragging a hand through the sand) on a landscape, as well as the intuitive realization of meaning of topographic contour lines, has proven to be engaging.

Computational fragment-based screening using RosettaLigand: the SAMPL3 challenge

NASA Astrophysics Data System (ADS)

Kumar, Ashutosh; Zhang, Kam Y. J.

2012-05-01

SAMPL3 fragment based virtual screening challenge provides a valuable opportunity for researchers to test their programs, methods and screening protocols in a blind testing environment. We participated in SAMPL3 challenge and evaluated our virtual fragment screening protocol, which involves RosettaLigand as the core component by screening a 500 fragments Maybridge library against bovine pancreatic trypsin. Our study reaffirmed that the real test for any virtual screening approach would be in a blind testing environment. The analyses presented in this paper also showed that virtual screening performance can be improved, if a set of known active compounds is available and parameters and methods that yield better enrichment are selected. Our study also highlighted that to achieve accurate orientation and conformation of ligands within a binding site, selecting an appropriate method to calculate partial charges is important. Another finding is that using multiple receptor ensembles in docking does not always yield better enrichment than individual receptors. On the basis of our results and retrospective analyses from SAMPL3 fragment screening challenge we anticipate that chances of success in a fragment screening process could be increased significantly with careful selection of receptor structures, protein flexibility, sufficient conformational sampling within binding pocket and accurate assignment of ligand and protein partial charges.

Effective virtual screening protocol for CYP2C9 ligands using a screening site constructed from flurbiprofen and S-warfarin pockets

NASA Astrophysics Data System (ADS)

Polgár, Tímea; Menyhárd, Dóra K.; Keserű, György M.

2007-09-01

An effective virtual screening protocol was developed against an extended active site of CYP2C9, which was derived from X-ray structures complexed with flubiprofen and S-warfarin. Virtual screening has been effectively supported by our structure-based pharmacophore model. Importance of hot residues identified by mutation data and structural analysis was first estimated in an enrichment study. Key role of Arg108 and Phe114 in ligand binding was also underlined. Our screening protocol successfully identified 76% of known CYP2C9 ligands in the top 1% of the ranked database resulting 76-fold enrichment relative to random situation. Relevance of the protocol was further confirmed in selectivity studies, when 89% of CYP2C9 ligands were retrieved from a mixture of CYP2C9 and CYP2C8 ligands, while only 22% of CYP2C8 ligands were found applying the structure-based pharmacophore constraints. Moderate discrimination of CYP2C9 ligands from CYP2C18 and CYP2C19 ligands could also be achieved extending the application domain of our virtual screening protocol for the entire CYP2C family. Our findings further demonstrate the existence of an active site comprising of at least two binding pockets and strengthens the need of involvement of protein flexibility in virtual screening.

Sense of presence and anxiety during virtual social interactions between a human and virtual humans.

PubMed

Morina, Nexhmedin; Brinkman, Willem-Paul; Hartanto, Dwi; Emmelkamp, Paul M G

2014-01-01

Virtual reality exposure therapy (VRET) has been shown to be effective in treatment of anxiety disorders. Yet, there is lack of research on the extent to which interaction between the individual and virtual humans can be successfully implanted to increase levels of anxiety for therapeutic purposes. This proof-of-concept pilot study aimed at examining levels of the sense of presence and anxiety during exposure to virtual environments involving social interaction with virtual humans and using different virtual reality displays. A non-clinical sample of 38 participants was randomly assigned to either a head-mounted display (HMD) with motion tracker and sterescopic view condition or a one-screen projection-based virtual reality display condition. Participants in both conditions engaged in free speech dialogues with virtual humans controlled by research assistants. It was hypothesized that exposure to virtual social interactions will elicit moderate levels of sense of presence and anxiety in both groups. Further it was expected that participants in the HMD condition will report higher scores of sense of presence and anxiety than participants in the one-screen projection-based display condition. Results revealed that in both conditions virtual social interactions were associated with moderate levels of sense of presence and anxiety. Additionally, participants in the HMD condition reported significantly higher levels of presence than those in the one-screen projection-based display condition (p = .001). However, contrary to the expectations neither the average level of anxiety nor the highest level of anxiety during exposure to social virtual environments differed between the groups (p = .97 and p = .75, respectively). The findings suggest that virtual social interactions can be successfully applied in VRET to enhance sense of presence and anxiety. Furthermore, our results indicate that one-screen projection-based displays can successfully activate levels of anxiety in social virtual environments. The outcome can prove helpful in using low-cost projection-based virtual reality environments for treating individuals with social phobia.

pROC-Chemotype Plots Enhance the Interpretability of Benchmarking Results in Structure-Based Virtual Screening.

PubMed

Ibrahim, Tamer M; Bauer, Matthias R; Dörr, Alexander; Veyisoglu, Erdem; Boeckler, Frank M

2015-11-23

Recently, we have reported a systematic comparison of molecular preparation protocols (using MOE or Maestro) in combination with two docking tools (GOLD or Glide), employing our DEKOIS 2.0 benchmark sets. Herein, we demonstrate how comparable settings of data preparation protocols can affect the profile and AUC of pROC curves based on variations in chemotype enrichment. We show how the recognition of different classes of chemotypes can affect the docking performance, particularly in the early enrichment, and monitor changes in this recognition behavior based on score normalization and rescoring strategies. For this, we have developed "pROC-Chemotype", which is an automated protocol that matches and visualizes ligand chemotype information together with potency classes in the pROC profiles obtained by docking. This tool enhances the understanding of the influence of chemotype recognition in early enrichment, but also reveals trends of impaired recognition of chemotype classes at the end of the score-ordered rank. Identifying such issues helps to devise score-normalization strategies to overcome this potential bias in an intuitive manner. Furthermore, strong perturbations in chemotype ranking between different methods can help to identify the underlying reasons (e.g., changes in the protonation/tautomerization state). It also assists in the selection of appropriate scoring functions that are capable to retrieve more potent and diverse hits. In summary, we demonstrate how this new tool can be utilized to identify and highlight chemotype-specific behavior, e.g., in dataset preparation. This can help to overcome some chemistry-related bias in virtual screening campaigns. pROC-Chemotype is made freely available at www.dekois.com.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Markidis, S.; Rizwan, U.

The use of virtual nuclear control room can be an effective and powerful tool for training personnel working in the nuclear power plants. Operators could experience and simulate the functioning of the plant, even in critical situations, without being in a real power plant or running any risk. 3D models can be exported to Virtual Reality formats and then displayed in the Virtual Reality environment providing an immersive 3D experience. However, two major limitations of this approach are that 3D models exhibit static textures, and they are not fully interactive and therefore cannot be used effectively in training personnel. Inmore » this paper we first describe a possible solution for embedding the output of a computer application in a 3D virtual scene, coupling real-world applications and VR systems. The VR system reported here grabs the output of an application running on an X server; creates a texture with the output and then displays it on a screen or a wall in the virtual reality environment. We then propose a simple model for providing interaction between the user in the VR system and the running simulator. This approach is based on the use of internet-based application that can be commanded by a laptop or tablet-pc added to the virtual environment. (authors)« less

Mapping, Awareness, And Virtualization Network Administrator Training Tool Virtualization Module

DTIC Science & Technology

2016-03-01

AND VIRTUALIZATION NETWORK ADMINISTRATOR TRAINING TOOL VIRTUALIZATION MODULE by Erik W. Berndt March 2016 Thesis Advisor: John Gibson...REPORT TYPE AND DATES COVERED Master’s thesis 4. TITLE AND SUBTITLE MAPPING, AWARENESS, AND VIRTUALIZATION NETWORK ADMINISTRATOR TRAINING TOOL... VIRTUALIZATION MODULE 5. FUNDING NUMBERS 6. AUTHOR(S) Erik W. Berndt 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Naval Postgraduate School

Virtual Reality as Innovative Approach to the Interior Designing

NASA Astrophysics Data System (ADS)

Kaleja, Pavol; Kozlovská, Mária

2017-06-01

We can observe significant potential of information and communication technologies (ICT) in interior designing field, by development of software and hardware virtual reality tools. Using ICT tools offer realistic perception of proposal in its initial idea (the study). A group of real-time visualization, supported by hardware tools like Oculus Rift HTC Vive, provides free walkthrough and movement in virtual interior with the possibility of virtual designing. By improving of ICT software tools for designing in virtual reality we can achieve still more realistic virtual environment. The contribution presented proposal of an innovative approach of interior designing in virtual reality, using the latest software and hardware ICT virtual reality technologies

Combining structure-based pharmacophore modeling, virtual screening, and in silico ADMET analysis to discover novel tetrahydro-quinoline based pyruvate kinase isozyme M2 activators with antitumor activity

PubMed Central

Chen, Can; Wang, Ting; Wu, Fengbo; Huang, Wei; He, Gu; Ouyang, Liang; Xiang, Mingli; Peng, Cheng; Jiang, Qinglin

2014-01-01

Compared with normal differentiated cells, cancer cells upregulate the expression of pyruvate kinase isozyme M2 (PKM2) to support glycolytic intermediates for anabolic processes, including the synthesis of nucleic acids, amino acids, and lipids. In this study, a combination of the structure-based pharmacophore modeling and a hybrid protocol of virtual screening methods comprised of pharmacophore model-based virtual screening, docking-based virtual screening, and in silico ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis were used to retrieve novel PKM2 activators from commercially available chemical databases. Tetrahydroquinoline derivatives were identified as potential scaffolds of PKM2 activators. Thus, the hybrid virtual screening approach was applied to screen the focused tetrahydroquinoline derivatives embedded in the ZINC database. Six hit compounds were selected from the final hits and experimental studies were then performed. Compound 8 displayed a potent inhibitory effect on human lung cancer cells. Following treatment with Compound 8, cell viability, apoptosis, and reactive oxygen species (ROS) production were examined in A549 cells. Finally, we evaluated the effects of Compound 8 on mice xenograft tumor models in vivo. These results may provide important information for further research on novel PKM2 activators as antitumor agents. PMID:25214764

Colon cancer screening

MedlinePlus

Screening for colon cancer; Colonoscopy - screening; Sigmoidoscopy - screening; Virtual colonoscopy - screening; Fecal immunochemical test; Stool DNA test; sDNA test; Colorectal cancer - screening; Rectal ...

Pharmacophore based approach to design inhibitors in crustaceans: an insight into the molt inhibition response to the receptor guanylyl cyclase.

PubMed

Shrivastava, Sajal; Princy, S Adline

2014-04-01

The first set of competitive inhibitors of molt inhibiting hormone (MIH) has been developed using the effective approaches such as Hip-Hop, virtual screening and manual alterations. Moreover, the conserved residues at 71 and 72 positions in the molt inhibiting hormone is known to be significant for selective inhibition of ecdysteroidogenesis; thus, the information from mutation and solution structure were used to generate common pharmacophore features. The geometry of the final six-feature pharmacophore was also found to be consistent with the homology-modeled MIH structures from various other decapod crustaceans. The Hypo-1, comprising six features hypothesis was carefully selected as a best pharmacophore model for virtual screening created on the basis of rank score and cluster processes. The hypothesis was validated and the database was virtually screened using this 3D query and the compounds were then manually altered to enhance the fit value. The hits obtained were further filtered for drug-likeness, which is expressed as physicochemical properties that contribute to favorable ADME/Tox profiles to eliminate the molecules exhibit toxicity and poor pharmacokinetics. In conclusion, the higher fit values of CI-1 (4.6), CI-4 (4.9) and CI-7 (4.2) in conjunction with better pharmacokinetic profile made these molecules practically helpful tool to increase production by accelerating molt in crustaceans. The use of feeding sub-therapeutic dosages of these growth enhancers can be very effectively implemented and certainly turn out to be a vital part of emerging nutritional strategies for economically important crustacean livestock.

RADER: a RApid DEcoy Retriever to facilitate decoy based assessment of virtual screening.

PubMed

Wang, Ling; Pang, Xiaoqian; Li, Yecheng; Zhang, Ziying; Tan, Wen

2017-04-15

Evaluation of the capacity for separating actives from challenging decoys is a crucial metric of performance related to molecular docking or a virtual screening workflow. The Directory of Useful Decoys (DUD) and its enhanced version (DUD-E) provide a benchmark for molecular docking, although they only contain a limited set of decoys for limited targets. DecoyFinder was released to compensate the limitations of DUD or DUD-E for building target-specific decoy sets. However, desirable query template design, generation of multiple decoy sets of similar quality, and computational speed remain bottlenecks, particularly when the numbers of queried actives and retrieved decoys increases to hundreds or more. Here, we developed a program suite called RApid DEcoy Retriever (RADER) to facilitate the decoy-based assessment of virtual screening. This program adopts a novel database-management regime that supports rapid and large-scale retrieval of decoys, enables high portability of databases, and provides multifaceted options for designing initial query templates from a large number of active ligands and generating subtle decoy sets. RADER provides two operational modes: as a command-line tool and on a web server. Validation of the performance and efficiency of RADER was also conducted and is described. RADER web server and a local version are freely available at http://rcidm.org/rader/ . lingwang@scut.edu.cn or went@scut.edu.cn . Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

NALDB: nucleic acid ligand database for small molecules targeting nucleic acid.

PubMed

Kumar Mishra, Subodh; Kumar, Amit

2016-01-01

Nucleic acid ligand database (NALDB) is a unique database that provides detailed information about the experimental data of small molecules that were reported to target several types of nucleic acid structures. NALDB is the first ligand database that contains ligand information for all type of nucleic acid. NALDB contains more than 3500 ligand entries with detailed pharmacokinetic and pharmacodynamic information such as target name, target sequence, ligand 2D/3D structure, SMILES, molecular formula, molecular weight, net-formal charge, AlogP, number of rings, number of hydrogen bond donor and acceptor, potential energy along with their Ki, Kd, IC50 values. All these details at single platform would be helpful for the development and betterment of novel ligands targeting nucleic acids that could serve as a potential target in different diseases including cancers and neurological disorders. With maximum 255 conformers for each ligand entry, our database is a multi-conformer database and can facilitate the virtual screening process. NALDB provides powerful web-based search tools that make database searching efficient and simplified using option for text as well as for structure query. NALDB also provides multi-dimensional advanced search tool which can screen the database molecules on the basis of molecular properties of ligand provided by database users. A 3D structure visualization tool has also been included for 3D structure representation of ligands. NALDB offers an inclusive pharmacological information and the structurally flexible set of small molecules with their three-dimensional conformers that can accelerate the virtual screening and other modeling processes and eventually complement the nucleic acid-based drug discovery research. NALDB can be routinely updated and freely available on bsbe.iiti.ac.in/bsbe/naldb/HOME.php. Database URL: http://bsbe.iiti.ac.in/bsbe/naldb/HOME.php. © The Author(s) 2016. Published by Oxford University Press.

Haptic, Virtual Interaction and Motor Imagery: Entertainment Tools and Psychophysiological Testing

PubMed Central

Invitto, Sara; Faggiano, Chiara; Sammarco, Silvia; De Luca, Valerio; De Paolis, Lucio T.

2016-01-01

In this work, the perception of affordances was analysed in terms of cognitive neuroscience during an interactive experience in a virtual reality environment. In particular, we chose a virtual reality scenario based on the Leap Motion controller: this sensor device captures the movements of the user’s hand and fingers, which are reproduced on a computer screen by the proper software applications. For our experiment, we employed a sample of 10 subjects matched by age and sex and chosen among university students. The subjects took part in motor imagery training and immersive affordance condition (a virtual training with Leap Motion and a haptic training with real objects). After each training sessions the subject performed a recognition task, in order to investigate event-related potential (ERP) components. The results revealed significant differences in the attentional components during the Leap Motion training. During Leap Motion session, latencies increased in the occipital lobes, which are entrusted to visual sensory; in contrast, latencies decreased in the frontal lobe, where the brain is mainly activated for attention and action planning. PMID:26999151

Haptic, Virtual Interaction and Motor Imagery: Entertainment Tools and Psychophysiological Testing.

PubMed

Invitto, Sara; Faggiano, Chiara; Sammarco, Silvia; De Luca, Valerio; De Paolis, Lucio T

2016-03-18

In this work, the perception of affordances was analysed in terms of cognitive neuroscience during an interactive experience in a virtual reality environment. In particular, we chose a virtual reality scenario based on the Leap Motion controller: this sensor device captures the movements of the user's hand and fingers, which are reproduced on a computer screen by the proper software applications. For our experiment, we employed a sample of 10 subjects matched by age and sex and chosen among university students. The subjects took part in motor imagery training and immersive affordance condition (a virtual training with Leap Motion and a haptic training with real objects). After each training sessions the subject performed a recognition task, in order to investigate event-related potential (ERP) components. The results revealed significant differences in the attentional components during the Leap Motion training. During Leap Motion session, latencies increased in the occipital lobes, which are entrusted to visual sensory; in contrast, latencies decreased in the frontal lobe, where the brain is mainly activated for attention and action planning.

[Selection of a melanine concentrating hormone receptor-1 (MCHR1) antagonists' focused library and its biological screening with AequoScreen].

PubMed

Flachner, Beáta; Hajdú, István; Dobi, Krisztina; Lorincz, Zsolt; Cseh, Sándor; Dormán, György

2013-01-01

Target focused libraries can be rapidly selected by 2D virtual screening methods from multimillion compounds' repositories if structures of active compounds are available. In the present study a multi-step virtual and in vitro screening cascade is reported to select Melanin Concentrating Hormone Receptor-1 (MCHR1) antagonists. The 2D similarity search combined with physicochemical parameter filtering is suitable for selecting candidates from multimillion compounds' repository. The seeds of the first round virtual screening were collected from the literature and commercial databases, while the seeds of the second round were the hits of the first round. In vitro screening underlined the efficiency of our approach, as in the second screening round the hit rate (8.6 %) significantly improved compared to the first round (1.9%), reaching the antagonist activity even below 10 nM.

Getting a handle on virtual tools: An examination of the neuronal activity associated with virtual tool use.

PubMed

Rallis, Austin; Fercho, Kelene A; Bosch, Taylor J; Baugh, Lee A

2018-01-31

Tool use is associated with three visual streams-dorso-dorsal, ventro-dorsal, and ventral visual streams. These streams are involved in processing online motor planning, action semantics, and tool semantics features, respectively. Little is known about the way in which the brain represents virtual tools. To directly assess this question, a virtual tool paradigm was created that provided the ability to manipulate tool components in isolation of one another. During functional magnetic resonance imaging (fMRI), adult participants performed a series of virtual tool manipulation tasks in which vision and movement kinematics of the tool were manipulated. Reaction time and hand movement direction were monitored while the tasks were performed. Functional imaging revealed that activity within all three visual streams was present, in a similar pattern to what would be expected with physical tool use. However, a previously unreported network of right-hemisphere activity was found including right inferior parietal lobule, middle and superior temporal gyri and supramarginal gyrus - regions well known to be associated with tool processing within the left hemisphere. These results provide evidence that both virtual and physical tools are processed within the same brain regions, though virtual tools recruit bilateral tool processing regions to a greater extent than physical tools. Copyright © 2017 Elsevier Ltd. All rights reserved.

Colorectal cancer screening with virtual colonoscopy

NASA Astrophysics Data System (ADS)

Ge, Yaorong; Vining, David J.; Ahn, David K.; Stelts, David R.

1999-05-01

Early detection and removal of colorectal polyps have been proven to reduce mortality from colorectal carcinoma (CRC), the second leading cause of cancer deaths in the United States. Unfortunately, traditional techniques for CRC examination (i.e., barium enema, sigmoidoscopy, and colonoscopy) are unsuitable for mass screening because of either low accuracy or poor public acceptance, costs, and risks. Virtual colonoscopy (VC) is a minimally invasive alternative that is based on tomographic scanning of the colon. After a patient's bowel is optimally cleansed and distended with gas, a fast tomographic scan, typically helical computed tomography (CT), of the abdomen is performed during a single breath-hold acquisition. Two-dimensional (2D) slices and three-dimensional (3D) rendered views of the colon lumen generated from the tomographic data are then examined for colorectal polyps. Recent clinical studies conducted at several institutions including ours have shown great potential for this technology to be an effective CRC screening tool. In this paper, we describe new methods to improve bowel preparation, colon lumen visualization, colon segmentation, and polyp detection. Our initial results show that VC with the new bowel preparation and imaging protocol is capable of achieving accuracy comparable to conventional colonoscopy and our new algorithms for image analysis contribute to increased accuracy and efficiency in VC examinations.

Docking ligands into flexible and solvated macromolecules. 7. Impact of protein flexibility and water molecules on docking-based virtual screening accuracy.

PubMed

Therrien, Eric; Weill, Nathanael; Tomberg, Anna; Corbeil, Christopher R; Lee, Devin; Moitessier, Nicolas

2014-11-24

The use of predictive computational methods in the drug discovery process is in a state of continual growth. Over the last two decades, an increasingly large number of docking tools have been developed to identify hits or optimize lead molecules through in-silico screening of chemical libraries to proteins. In recent years, the focus has been on implementing protein flexibility and water molecules. Our efforts led to the development of Fitted first reported in 2007 and further developed since then. In this study, we wished to evaluate the impact of protein flexibility and occurrence of water molecules on the accuracy of the Fitted docking program to discriminate active compounds from inactive compounds in virtual screening (VS) campaigns. For this purpose, a total of 171 proteins cocrystallized with small molecules representing 40 unique enzymes and receptors as well as sets of known ligands and decoys were selected from the Protein Data Bank (PDB) and the Directory of Useful Decoys (DUD), respectively. This study revealed that implementing displaceable crystallographic or computationally placed particle water molecules and protein flexibility can improve the enrichment in active compounds. In addition, an informed decision based on library diversity or research objectives (hit discovery vs lead optimization) on which implementation to use may lead to significant improvements.

Identification of Human IKK-2 Inhibitors of Natural Origin (Part I): Modeling of the IKK-2 Kinase Domain, Virtual Screening and Activity Assays

PubMed Central

Sala, Esther; Guasch, Laura; Iwaszkiewicz, Justyna; Mulero, Miquel; Salvadó, Maria-Josepa; Pinent, Montserrat; Zoete, Vincent; Grosdidier, Aurélien; Garcia-Vallvé, Santiago; Michielin, Olivier; Pujadas, Gerard

2011-01-01

Background Their large scaffold diversity and properties, such as structural complexity and drug similarity, form the basis of claims that natural products are ideal starting points for drug design and development. Consequently, there has been great interest in determining whether such molecules show biological activity toward protein targets of pharmacological relevance. One target of particular interest is hIKK-2, a serine-threonine protein kinase belonging to the IKK complex that is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Indeed, this has led to the development of synthetic ATP-competitive inhibitors for hIKK-2. Therefore, the main goals of this study were (a) to use virtual screening to identify potential hIKK-2 inhibitors of natural origin that compete with ATP and (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits. Methodology/Principal Findings We thus predicted that 1,061 out of the 89,425 natural products present in the studied database would inhibit hIKK-2 with good ADMET properties. Notably, when these 1,061 molecules were merged with the 98 synthetic hIKK-2 inhibitors used in this study and the resulting set was classified into ten clusters according to chemical similarity, there were three clusters that contained only natural products. Five molecules from these three clusters (for which no anti-inflammatory activity has been previously described) were then selected for in vitro activity testing, in which three out of the five molecules were shown to inhibit hIKK-2. Conclusions/Significance We demonstrated that our virtual-screening protocol was successful in identifying lead compounds for developing new inhibitors for hIKK-2, a target of great interest in medicinal chemistry. Additionally, all the tools developed during the current study (i.e., the homology model for the hIKK-2 kinase domain and the pharmacophore) will be made available to interested readers upon request. PMID:21390216

SAMPL4 & DOCK3.7: lessons for automated docking procedures

NASA Astrophysics Data System (ADS)

Coleman, Ryan G.; Sterling, Teague; Weiss, Dahlia R.

2014-03-01

The SAMPL4 challenges were used to test current automated methods for solvation energy, virtual screening, pose and affinity prediction of the molecular docking pipeline DOCK 3.7. Additionally, first-order models of binding affinity were proposed as milestones for any method predicting binding affinity. Several important discoveries about the molecular docking software were made during the challenge: (1) Solvation energies of ligands were five-fold worse than any other method used in SAMPL4, including methods that were similarly fast, (2) HIV Integrase is a challenging target, but automated docking on the correct allosteric site performed well in terms of virtual screening and pose prediction (compared to other methods) but affinity prediction, as expected, was very poor, (3) Molecular docking grid sizes can be very important, serious errors were discovered with default settings that have been adjusted for all future work. Overall, lessons from SAMPL4 suggest many changes to molecular docking tools, not just DOCK 3.7, that could improve the state of the art. Future difficulties and projects will be discussed.

Fragment-Based Docking: Development of the CHARMMing Web User Interface as a Platform for Computer-Aided Drug Design

PubMed Central

2015-01-01

Web-based user interfaces to scientific applications are important tools that allow researchers to utilize a broad range of software packages with just an Internet connection and a browser.1 One such interface, CHARMMing (CHARMM interface and graphics), facilitates access to the powerful and widely used molecular software package CHARMM. CHARMMing incorporates tasks such as molecular structure analysis, dynamics, multiscale modeling, and other techniques commonly used by computational life scientists. We have extended CHARMMing’s capabilities to include a fragment-based docking protocol that allows users to perform molecular docking and virtual screening calculations either directly via the CHARMMing Web server or on computing resources using the self-contained job scripts generated via the Web interface. The docking protocol was evaluated by performing a series of “re-dockings” with direct comparison to top commercial docking software. Results of this evaluation showed that CHARMMing’s docking implementation is comparable to many widely used software packages and validates the use of the new CHARMM generalized force field for docking and virtual screening. PMID:25151852

Tautomer preference in PDB complexes and its impact on structure-based drug discovery.

PubMed

Milletti, Francesca; Vulpetti, Anna

2010-06-28

Tautomer enrichment is a key step of ligand preparation prior to virtual screening. In this paper, we have investigated how tautomer preference in various media (water, gas phase, and crystal) compares to tautomer preference at the active site of the protein by analyzing the different possible H-bonding contacts for a set of 13 tautomeric structures. In addition, we have explored the impact of four different protocols for the enumeration of tautomers in virtual screening by using Flap, Glide, and Gold as docking tools on seven targets of the DUD data set. Excluding targets in which the binding does not involve tautomeric atoms (HSP90, p38, and VEGFR2), we found that the average receiver operating characteristic curve enrichment at 10% was 0.25 (Gold), 0.24 (Glide), and 0.50 (Flap) by considering only tautomers predicted to be unstable in water versus 0.41 (Gold), 0.56 (Glide), 0.51 (Flap) by limiting the enumeration process only to the predicted most stable tautomer. The inclusion of all tautomers (stable and unstable) yielded slightly poorer results than considering only the most stable form in water.

Fragment-based docking: development of the CHARMMing Web user interface as a platform for computer-aided drug design.

PubMed

Pevzner, Yuri; Frugier, Emilie; Schalk, Vinushka; Caflisch, Amedeo; Woodcock, H Lee

2014-09-22

Web-based user interfaces to scientific applications are important tools that allow researchers to utilize a broad range of software packages with just an Internet connection and a browser. One such interface, CHARMMing (CHARMM interface and graphics), facilitates access to the powerful and widely used molecular software package CHARMM. CHARMMing incorporates tasks such as molecular structure analysis, dynamics, multiscale modeling, and other techniques commonly used by computational life scientists. We have extended CHARMMing's capabilities to include a fragment-based docking protocol that allows users to perform molecular docking and virtual screening calculations either directly via the CHARMMing Web server or on computing resources using the self-contained job scripts generated via the Web interface. The docking protocol was evaluated by performing a series of "re-dockings" with direct comparison to top commercial docking software. Results of this evaluation showed that CHARMMing's docking implementation is comparable to many widely used software packages and validates the use of the new CHARMM generalized force field for docking and virtual screening.

bcl::Cluster : A method for clustering biological molecules coupled with visualization in the Pymol Molecular Graphics System.

PubMed

Alexander, Nathan; Woetzel, Nils; Meiler, Jens

2011-02-01

Clustering algorithms are used as data analysis tools in a wide variety of applications in Biology. Clustering has become especially important in protein structure prediction and virtual high throughput screening methods. In protein structure prediction, clustering is used to structure the conformational space of thousands of protein models. In virtual high throughput screening, databases with millions of drug-like molecules are organized by structural similarity, e.g. common scaffolds. The tree-like dendrogram structure obtained from hierarchical clustering can provide a qualitative overview of the results, which is important for focusing detailed analysis. However, in practice it is difficult to relate specific components of the dendrogram directly back to the objects of which it is comprised and to display all desired information within the two dimensions of the dendrogram. The current work presents a hierarchical agglomerative clustering method termed bcl::Cluster. bcl::Cluster utilizes the Pymol Molecular Graphics System to graphically depict dendrograms in three dimensions. This allows simultaneous display of relevant biological molecules as well as additional information about the clusters and the members comprising them.

Evaluation and optimization of virtual screening workflows with DEKOIS 2.0--a public library of challenging docking benchmark sets.

PubMed

Bauer, Matthias R; Ibrahim, Tamer M; Vogel, Simon M; Boeckler, Frank M

2013-06-24

The application of molecular benchmarking sets helps to assess the actual performance of virtual screening (VS) workflows. To improve the efficiency of structure-based VS approaches, the selection and optimization of various parameters can be guided by benchmarking. With the DEKOIS 2.0 library, we aim to further extend and complement the collection of publicly available decoy sets. Based on BindingDB bioactivity data, we provide 81 new and structurally diverse benchmark sets for a wide variety of different target classes. To ensure a meaningful selection of ligands, we address several issues that can be found in bioactivity data. We have improved our previously introduced DEKOIS methodology with enhanced physicochemical matching, now including the consideration of molecular charges, as well as a more sophisticated elimination of latent actives in the decoy set (LADS). We evaluate the docking performance of Glide, GOLD, and AutoDock Vina with our data sets and highlight existing challenges for VS tools. All DEKOIS 2.0 benchmark sets will be made accessible at http://www.dekois.com.

mRAISE: an alternative algorithmic approach to ligand-based virtual screening

NASA Astrophysics Data System (ADS)

von Behren, Mathias M.; Bietz, Stefan; Nittinger, Eva; Rarey, Matthias

2016-08-01

Ligand-based virtual screening is a well established method to find new lead molecules in todays drug discovery process. In order to be applicable in day to day practice, such methods have to face multiple challenges. The most important part is the reliability of the results, which can be shown and compared in retrospective studies. Furthermore, in the case of 3D methods, they need to provide biologically relevant molecular alignments of the ligands, that can be further investigated by a medicinal chemist. Last but not least, they have to be able to screen large databases in reasonable time. Many algorithms for ligand-based virtual screening have been proposed in the past, most of them based on pairwise comparisons. Here, a new method is introduced called mRAISE. Based on structural alignments, it uses a descriptor-based bitmap search engine (RAISE) to achieve efficiency. Alignments created on the fly by the search engine get evaluated with an independent shape-based scoring function also used for ranking of compounds. The correct ranking as well as the alignment quality of the method are evaluated and compared to other state of the art methods. On the commonly used Directory of Useful Decoys dataset mRAISE achieves an average area under the ROC curve of 0.76, an average enrichment factor at 1 % of 20.2 and an average hit rate at 1 % of 55.5. With these results, mRAISE is always among the top performing methods with available data for comparison. To access the quality of the alignments calculated by ligand-based virtual screening methods, we introduce a new dataset containing 180 prealigned ligands for 11 diverse targets. Within the top ten ranked conformations, the alignment closest to X-ray structure calculated with mRAISE has a root-mean-square deviation of less than 2.0 Å for 80.8 % of alignment pairs and achieves a median of less than 2.0 Å for eight of the 11 cases. The dataset used to rate the quality of the calculated alignments is freely available at http://www.zbh.uni-hamburg.de/mraise-dataset.html. The table of all PDB codes contained in the ensembles can be found in the supplementary material. The software tool mRAISE is freely available for evaluation purposes and academic use (see http://www.zbh.uni-hamburg.de/raise).

The Texas-Indiana Virtual STAR Center: Zebrafish Models for Developmental Toxicity Screening

EPA Pesticide Factsheets

The Texas-Indiana Virtual STAR Center: Zebrafish Models for Developmental Toxicity Screening (Presented by Maria Bondesson Bolin, Ph.D, University of Houston, Center for Nuclear Receptors and Cell Signaling) (3/22/2012)

Virtual screening of B-Raf kinase inhibitors: A combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy calculation studies.

PubMed

Zhang, Wen; Qiu, Kai-Xiong; Yu, Fang; Xie, Xiao-Guang; Zhang, Shu-Qun; Chen, Ya-Juan; Xie, Hui-Ding

2017-10-01

B-Raf kinase has been identified as an important target in recent cancer treatment. In order to discover structurally diverse and novel B-Raf inhibitors (BRIs), a virtual screening of BRIs against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy (ΔG bind ) calculation studies in this work. After the virtual screening, six promising hit compounds were obtained, which were then tested for inhibitory activities of A375 cell lines. In the result, five hit compounds show good biological activities (IC 50 <50μM). The present method of virtual screening can be applied to find structurally diverse inhibitors, and the obtained five structurally diverse compounds are expected to develop novel BRIs. Copyright © 2017. Published by Elsevier Ltd.

Stereoscopic vascular models of the head and neck: A computed tomography angiography visualization.

PubMed

Cui, Dongmei; Lynch, James C; Smith, Andrew D; Wilson, Timothy D; Lehman, Michael N

2016-01-01

Computer-assisted 3D models are used in some medical and allied health science schools; however, they are often limited to online use and 2D flat screen-based imaging. Few schools take advantage of 3D stereoscopic learning tools in anatomy education and clinically relevant anatomical variations when teaching anatomy. A new approach to teaching anatomy includes use of computed tomography angiography (CTA) images of the head and neck to create clinically relevant 3D stereoscopic virtual models. These high resolution images of the arteries can be used in unique and innovative ways to create 3D virtual models of the vasculature as a tool for teaching anatomy. Blood vessel 3D models are presented stereoscopically in a virtual reality environment, can be rotated 360° in all axes, and magnified according to need. In addition, flexible views of internal structures are possible. Images are displayed in a stereoscopic mode, and students view images in a small theater-like classroom while wearing polarized 3D glasses. Reconstructed 3D models enable students to visualize vascular structures with clinically relevant anatomical variations in the head and neck and appreciate spatial relationships among the blood vessels, the skull and the skin. © 2015 American Association of Anatomists.

2D and 3D virtual interactive laboratories of physics on Unity platform

NASA Astrophysics Data System (ADS)

González, J. D.; Escobar, J. H.; Sánchez, H.; De la Hoz, J.; Beltrán, J. R.

2017-12-01

Using the cross-platform game engine Unity, we develop virtual laboratories for PC, consoles, mobile devices and website as an innovative tool to study physics. There is extensive uptake of ICT in the teaching of science and its impact on the learning, and considering the limited availability of laboratories for physics teaching and the difficulties this causes in the learning of school students, we design the virtual laboratories to enhance studentâĂŹs knowledge of concepts in physics. To achieve this goal, we use Unity due to provide support bump mapping, reflection mapping, parallax mapping, dynamics shadows using shadows maps, full-screen post-processing effects and render-to-texture. Unity can use the best variant for the current video hardware and, if none are compatible, to use an alternative shader that may sacrifice features for performance. The control over delivery to mobile devices, web browsers, consoles and desktops is the main reason Unity is the best option among the same kind cross-platform. Supported platforms include Android, Apple TV, Linux, iOS, Nintendo 3DS line, macOS, PlayStation 4, Windows Phone 8, Wii but also an asset server and Nvidia’s PhysX physics engine which is the most relevant tool on Unity for our PhysLab.

Machine Learning-based Virtual Screening and Its Applications to Alzheimer's Drug Discovery: A Review.

PubMed

Carpenter, Kristy A; Huang, Xudong

2018-06-07

Virtual Screening (VS) has emerged as an important tool in the drug development process, as it conducts efficient in silico searches over millions of compounds, ultimately increasing yields of potential drug leads. As a subset of Artificial Intelligence (AI), Machine Learning (ML) is a powerful way of conducting VS for drug leads. ML for VS generally involves assembling a filtered training set of compounds, comprised of known actives and inactives. After training the model, it is validated and, if sufficiently accurate, used on previously unseen databases to screen for novel compounds with desired drug target binding activity. The study aims to review ML-based methods used for VS and applications to Alzheimer's disease (AD) drug discovery. To update the current knowledge on ML for VS, we review thorough backgrounds, explanations, and VS applications of the following ML techniques: Naïve Bayes (NB), k-Nearest Neighbors (kNN), Support Vector Machines (SVM), Random Forests (RF), and Artificial Neural Networks (ANN). All techniques have found success in VS, but the future of VS is likely to lean more heavily toward the use of neural networks - and more specifically, Convolutional Neural Networks (CNN), which are a subset of ANN that utilize convolution. We additionally conceptualize a work flow for conducting ML-based VS for potential therapeutics of for AD, a complex neurodegenerative disease with no known cure and prevention. This both serves as an example of how to apply the concepts introduced earlier in the review and as a potential workflow for future implementation. Different ML techniques are powerful tools for VS, and they have advantages and disadvantages albeit. ML-based VS can be applied to AD drug development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Impact of virtual microscopy with conventional microscopy on student learning in dental histology.

PubMed

Hande, Alka Harish; Lohe, Vidya K; Chaudhary, Minal S; Gawande, Madhuri N; Patil, Swati K; Zade, Prajakta R

2017-01-01

In dental histology, the assimilation of histological features of different dental hard and soft tissues is done by conventional microscopy. This traditional method of learning prevents the students from screening the entire slide and change of magnification. To address these drawbacks, modification in conventional microscopy has evolved and become motivation for changing the learning tool. Virtual microscopy is the technique in which there is complete digitization of the microscopic glass slide, which can be analyzed on a computer. This research is designed to evaluate the effectiveness of virtual microscopy with conventional microscopy on student learning in dental histology. A cohort of 105 students were included and randomized into three groups: A, B, and C. Group A students studied the microscopic features of oral histologic lesions by conventional microscopy, Group B by virtual microscopy, and Group C by both conventional and virtual microscopy. The students' understanding of the subject was evaluated by a prepared questionnaire. The effectiveness of the study designs on knowledge gains and satisfaction levels was assessed by statistical assessment of differences in mean test scores. The difference in score between Groups A, B, and C at pre- and post-test was highly significant. This enhanced understanding of the subject may be due to benefits of using virtual microscopy in teaching histology. The augmentation of conventional microscopy with virtual microscopy shows enhancement of the understanding of the subject as compared to the use of conventional microscopy and virtual microscopy alone.

Extending the Body to Virtual Tools Using a Robotic Surgical Interface: Evidence from the Crossmodal Congruency Task

PubMed Central

Sengül, Ali; van Elk, Michiel; Rognini, Giulio; Aspell, Jane Elizabeth; Bleuler, Hannes; Blanke, Olaf

2012-01-01

The effects of real-world tool use on body or space representations are relatively well established in cognitive neuroscience. Several studies have shown, for example, that active tool use results in a facilitated integration of multisensory information in peripersonal space, i.e. the space directly surrounding the body. However, it remains unknown to what extent similar mechanisms apply to the use of virtual-robotic tools, such as those used in the field of surgical robotics, in which a surgeon may use bimanual haptic interfaces to control a surgery robot at a remote location. This paper presents two experiments in which participants used a haptic handle, originally designed for a commercial surgery robot, to control a virtual tool. The integration of multisensory information related to the virtual-robotic tool was assessed by means of the crossmodal congruency task, in which subjects responded to tactile vibrations applied to their fingers while ignoring visual distractors superimposed on the tip of the virtual-robotic tool. Our results show that active virtual-robotic tool use changes the spatial modulation of the crossmodal congruency effects, comparable to changes in the representation of peripersonal space observed during real-world tool use. Moreover, when the virtual-robotic tools were held in a crossed position, the visual distractors interfered strongly with tactile stimuli that was connected with the hand via the tool, reflecting a remapping of peripersonal space. Such remapping was not only observed when the virtual-robotic tools were actively used (Experiment 1), but also when passively held the tools (Experiment 2). The present study extends earlier findings on the extension of peripersonal space from physical and pointing tools to virtual-robotic tools using techniques from haptics and virtual reality. We discuss our data with respect to learning and human factors in the field of surgical robotics and discuss the use of new technologies in the field of cognitive neuroscience. PMID:23227142

Extending the body to virtual tools using a robotic surgical interface: evidence from the crossmodal congruency task.

PubMed

Sengül, Ali; van Elk, Michiel; Rognini, Giulio; Aspell, Jane Elizabeth; Bleuler, Hannes; Blanke, Olaf

2012-01-01

The effects of real-world tool use on body or space representations are relatively well established in cognitive neuroscience. Several studies have shown, for example, that active tool use results in a facilitated integration of multisensory information in peripersonal space, i.e. the space directly surrounding the body. However, it remains unknown to what extent similar mechanisms apply to the use of virtual-robotic tools, such as those used in the field of surgical robotics, in which a surgeon may use bimanual haptic interfaces to control a surgery robot at a remote location. This paper presents two experiments in which participants used a haptic handle, originally designed for a commercial surgery robot, to control a virtual tool. The integration of multisensory information related to the virtual-robotic tool was assessed by means of the crossmodal congruency task, in which subjects responded to tactile vibrations applied to their fingers while ignoring visual distractors superimposed on the tip of the virtual-robotic tool. Our results show that active virtual-robotic tool use changes the spatial modulation of the crossmodal congruency effects, comparable to changes in the representation of peripersonal space observed during real-world tool use. Moreover, when the virtual-robotic tools were held in a crossed position, the visual distractors interfered strongly with tactile stimuli that was connected with the hand via the tool, reflecting a remapping of peripersonal space. Such remapping was not only observed when the virtual-robotic tools were actively used (Experiment 1), but also when passively held the tools (Experiment 2). The present study extends earlier findings on the extension of peripersonal space from physical and pointing tools to virtual-robotic tools using techniques from haptics and virtual reality. We discuss our data with respect to learning and human factors in the field of surgical robotics and discuss the use of new technologies in the field of cognitive neuroscience.

Discovery of novel human acrosin inhibitors by virtual screening

NASA Astrophysics Data System (ADS)

Liu, Xuefei; Dong, Guoqiang; Zhang, Jue; Qi, Jingjing; Zheng, Canhui; Zhou, Youjun; Zhu, Ju; Sheng, Chunquan; Lü, Jiaguo

2011-10-01

Human acrosin is an attractive target for the discovery of male contraceptive drugs. For the first time, structure-based drug design was applied to discover structurally diverse human acrosin inhibitors. A parallel virtual screening strategy in combination with pharmacophore-based and docking-based techniques was used to screen the SPECS database. From 16 compounds selected by virtual screening, a total of 10 compounds were found to be human acrosin inhibitors. Compound 2 was found to be the most potent hit (IC50 = 14 μM) and its binding mode was investigated by molecular dynamics simulations. The hit interacted with human acrosin mainly through hydrophobic and hydrogen-bonding interactions, which provided a good starting structure for further optimization studies.

The CAVE (TM) automatic virtual environment: Characteristics and applications

NASA Technical Reports Server (NTRS)

Kenyon, Robert V.

1995-01-01

Virtual reality may best be defined as the wide-field presentation of computer-generated, multi-sensory information that tracks a user in real time. In addition to the more well-known modes of virtual reality -- head-mounted displays and boom-mounted displays -- the Electronic Visualization Laboratory at the University of Illinois at Chicago recently introduced a third mode: a room constructed from large screens on which the graphics are projected on to three walls and the floor. The CAVE is a multi-person, room sized, high resolution, 3D video and audio environment. Graphics are rear projected in stereo onto three walls and the floor, and viewed with stereo glasses. As a viewer wearing a location sensor moves within its display boundaries, the correct perspective and stereo projections of the environment are updated, and the image moves with and surrounds the viewer. The other viewers in the CAVE are like passengers in a bus, along for the ride. 'CAVE,' the name selected for the virtual reality theater, is both a recursive acronym (Cave Automatic Virtual Environment) and a reference to 'The Simile of the Cave' found in Plato's 'Republic,' in which the philosopher explores the ideas of perception, reality, and illusion. Plato used the analogy of a person facing the back of a cave alive with shadows that are his/her only basis for ideas of what real objects are. Rather than having evolved from video games or flight simulation, the CAVE has its motivation rooted in scientific visualization and the SIGGRAPH 92 Showcase effort. The CAVE was designed to be a useful tool for scientific visualization. The Showcase event was an experiment; the Showcase chair and committee advocated an environment for computational scientists to interactively present their research at a major professional conference in a one-to-many format on high-end workstations attached to large projection screens. The CAVE was developed as a 'virtual reality theater' with scientific content and projection that met the criteria of Showcase.

How to Achieve Better Results Using Pass-Based Virtual Screening: Case Study for Kinase Inhibitors

NASA Astrophysics Data System (ADS)

Pogodin, Pavel V.; Lagunin, Alexey A.; Rudik, Anastasia V.; Filimonov, Dmitry A.; Druzhilovskiy, Dmitry S.; Nicklaus, Mark C.; Poroikov, Vladimir V.

2018-04-01

Discovery of new pharmaceutical substances is currently boosted by the possibility of utilization of the Synthetically Accessible Virtual Inventory (SAVI) library, which includes about 283 million molecules, each annotated with a proposed synthetic one-step route from commercially available starting materials. The SAVI database is well-suited for ligand-based methods of virtual screening to select molecules for experimental testing. In this study, we compare the performance of three approaches for the analysis of structure-activity relationships that differ in their criteria for selecting of “active” and “inactive” compounds included in the training sets. PASS (Prediction of Activity Spectra for Substances), which is based on a modified Naïve Bayes algorithm, was applied since it had been shown to be robust and to provide good predictions of many biological activities based on just the structural formula of a compound even if the information in the training set is incomplete. We used different subsets of kinase inhibitors for this case study because many data are currently available on this important class of drug-like molecules. Based on the subsets of kinase inhibitors extracted from the ChEMBL 20 database we performed the PASS training, and then applied the model to ChEMBL 23 compounds not yet present in ChEMBL 20 to identify novel kinase inhibitors. As one may expect, the best prediction accuracy was obtained if only the experimentally confirmed active and inactive compounds for distinct kinases in the training procedure were used. However, for some kinases, reasonable results were obtained even if we used merged training sets, in which we designated as inactives the compounds not tested against the particular kinase. Thus, depending on the availability of data for a particular biological activity, one may choose the first or the second approach for creating ligand-based computational tools to achieve the best possible results in virtual screening.

How to benchmark methods for structure-based virtual screening of large compound libraries.

PubMed

Christofferson, Andrew J; Huang, Niu

2012-01-01

Structure-based virtual screening is a useful computational technique for ligand discovery. To systematically evaluate different docking approaches, it is important to have a consistent benchmarking protocol that is both relevant and unbiased. Here, we describe the designing of a benchmarking data set for docking screen assessment, a standard docking screening process, and the analysis and presentation of the enrichment of annotated ligands among a background decoy database.

Tangible display systems: bringing virtual surfaces into the real world

NASA Astrophysics Data System (ADS)

Ferwerda, James A.

2012-03-01

We are developing tangible display systems that enable natural interaction with virtual surfaces. Tangible display systems are based on modern mobile devices that incorporate electronic image displays, graphics hardware, tracking systems, and digital cameras. Custom software allows the orientation of a device and the position of the observer to be tracked in real-time. Using this information, realistic images of surfaces with complex textures and material properties illuminated by environment-mapped lighting, can be rendered to the screen at interactive rates. Tilting or moving in front of the device produces realistic changes in surface lighting and material appearance. In this way, tangible displays allow virtual surfaces to be observed and manipulated as naturally as real ones, with the added benefit that surface geometry and material properties can be modified in real-time. We demonstrate the utility of tangible display systems in four application areas: material appearance research; computer-aided appearance design; enhanced access to digital library and museum collections; and new tools for digital artists.

Similarity searching and scaffold hopping in synthetically accessible combinatorial chemistry spaces.

PubMed

Boehm, Markus; Wu, Tong-Ying; Claussen, Holger; Lemmen, Christian

2008-04-24

Large collections of combinatorial libraries are an integral element in today's pharmaceutical industry. It is of great interest to perform similarity searches against all virtual compounds that are synthetically accessible by any such library. Here we describe the successful application of a new software tool CoLibri on 358 combinatorial libraries based on validated reaction protocols to create a single chemistry space containing over 10 (12) possible products. Similarity searching with FTrees-FS allows the systematic exploration of this space without the need to enumerate all product structures. The search result is a set of virtual hits which are synthetically accessible by one or more of the existing reaction protocols. Grouping these virtual hits by their synthetic protocols allows the rapid design and synthesis of multiple follow-up libraries. Such library ideas support hit-to-lead design efforts for tasks like follow-up from high-throughput screening hits or scaffold hopping from one hit to another attractive series.

Stepping into the virtual unknown: feasibility study of a virtual reality-based test of ocular misalignment.

PubMed

Nesaratnam, N; Thomas, P; Vivian, A

2017-10-01

IntroductionDissociated tests of strabismus provide valuable information for diagnosis and monitoring of ocular misalignment in patients with normal retinal correspondence. However, they are vulnerable to operator error and rely on a fixed head position. Virtual reality headsets obviate the need for head fixation, while providing other clear theoretical advantages, including complete control over the illumination and targets presented for the patient's interaction.PurposeWe compared the performance of a virtual reality-based test of ocular misalignment to that of the traditional Lees screen, to establish the feasibility of using virtual reality technology in ophthalmic settings in the future.MethodsThree patients underwent a traditional Lees screen test, and a virtual reality headset-based test of ocular motility. The virtual reality headset-based programme consisted of an initial test to measure horizontal and vertical deviation, followed by a test for torsion.ResultsThe pattern of deviation obtained using the virtual reality-based test showed agreement with that obtained from the Lees screen for patients with a fourth nerve palsy, comitant esotropia, and restrictive thyroid eye disease.ConclusionsThis study reports the first use of a virtual reality headset in assessing ocular misalignment, and demonstrates that it is a feasible dissociative test of strabismus.

Trainable structure-activity relationship model for virtual screening of CYP3A4 inhibition.

PubMed

Didziapetris, Remigijus; Dapkunas, Justas; Sazonovas, Andrius; Japertas, Pranas

2010-11-01

A new structure-activity relationship model predicting the probability for a compound to inhibit human cytochrome P450 3A4 has been developed using data for >800 compounds from various literature sources and tested on PubChem screening data. Novel GALAS (Global, Adjusted Locally According to Similarity) modeling methodology has been used, which is a combination of baseline global QSAR model and local similarity based corrections. GALAS modeling method allows forecasting the reliability of prediction thus defining the model applicability domain. For compounds within this domain the statistical results of the final model approach the data consistency between experimental data from literature and PubChem datasets with the overall accuracy of 89%. However, the original model is applicable only for less than a half of PubChem database. Since the similarity correction procedure of GALAS modeling method allows straightforward model training, the possibility to expand the applicability domain has been investigated. Experimental data from PubChem dataset served as an example of in-house high-throughput screening data. The model successfully adapted itself to both data classified using the same and different IC₅₀ threshold compared with the training set. In addition, adjustment of the CYP3A4 inhibition model to compounds with a novel chemical scaffold has been demonstrated. The reported GALAS model is proposed as a useful tool for virtual screening of compounds for possible drug-drug interactions even prior to the actual synthesis.

Enrichment assessment of multiple virtual screening strategies for Toll-like receptor 8 agonists based on a maximal unbiased benchmarking data set.

PubMed

Pei, Fen; Jin, Hongwei; Zhou, Xin; Xia, Jie; Sun, Lidan; Liu, Zhenming; Zhang, Liangren

2015-11-01

Toll-like receptor 8 agonists, which activate adaptive immune responses by inducing robust production of T-helper 1-polarizing cytokines, are promising candidates for vaccine adjuvants. As the binding site of toll-like receptor 8 is large and highly flexible, virtual screening by individual method has inevitable limitations; thus, a comprehensive comparison of different methods may provide insights into seeking effective strategy for the discovery of novel toll-like receptor 8 agonists. In this study, the performance of knowledge-based pharmacophore, shape-based 3D screening, and combined strategies was assessed against a maximum unbiased benchmarking data set containing 13 actives and 1302 decoys specialized for toll-like receptor 8 agonists. Prior structure-activity relationship knowledge was involved in knowledge-based pharmacophore generation, and a set of antagonists was innovatively used to verify the selectivity of the selected knowledge-based pharmacophore. The benchmarking data set was generated from our recently developed 'mubd-decoymaker' protocol. The enrichment assessment demonstrated a considerable performance through our selected three-layer virtual screening strategy: knowledge-based pharmacophore (Phar1) screening, shape-based 3D similarity search (Q4_combo), and then a Gold docking screening. This virtual screening strategy could be further employed to perform large-scale database screening and to discover novel toll-like receptor 8 agonists. © 2015 John Wiley & Sons A/S.

Prospective virtual screening for novel p53-MDM2 inhibitors using ultrafast shape recognition

NASA Astrophysics Data System (ADS)

Patil, Sachin P.; Ballester, Pedro J.; Kerezsi, Cassidy R.

2014-02-01

The p53 protein, known as the guardian of genome, is mutated or deleted in approximately 50 % of human tumors. In the rest of the cancers, p53 is expressed in its wild-type form, but its function is inhibited by direct binding with the murine double minute 2 (MDM2) protein. Therefore, inhibition of the p53-MDM2 interaction, leading to the activation of tumor suppressor p53 protein presents a fundamentally novel therapeutic strategy against several types of cancers. The present study utilized ultrafast shape recognition (USR), a virtual screening technique based on ligand-receptor 3D shape complementarity, to screen DrugBank database for novel p53-MDM2 inhibitors. Specifically, using 3D shape of one of the most potent crystal ligands of MDM2, MI-63, as the query molecule, six compounds were identified as potential p53-MDM2 inhibitors. These six USR hits were then subjected to molecular modeling investigations through flexible receptor docking followed by comparative binding energy analysis. These studies suggested a potential role of the USR-selected molecules as p53-MDM2 inhibitors. This was further supported by experimental tests showing that the treatment of human colon tumor cells with the top USR hit, telmisartan, led to a dose-dependent cell growth inhibition in a p53-dependent manner. It is noteworthy that telmisartan has a long history of safe human use as an approved anti-hypertension drug and thus may present an immediate clinical potential as a cancer therapeutic. Furthermore, it could also serve as a structurally-novel lead molecule for the development of more potent, small-molecule p53-MDM2 inhibitors against variety of cancers. Importantly, the present study demonstrates that the adopted USR-based virtual screening protocol is a useful tool for hit identification in the domain of small molecule p53-MDM2 inhibitors.

Chemical Space: Big Data Challenge for Molecular Diversity.

PubMed

Awale, Mahendra; Visini, Ricardo; Probst, Daniel; Arús-Pous, Josep; Reymond, Jean-Louis

2017-10-25

Chemical space describes all possible molecules as well as multi-dimensional conceptual spaces representing the structural diversity of these molecules. Part of this chemical space is available in public databases ranging from thousands to billions of compounds. Exploiting these databases for drug discovery represents a typical big data problem limited by computational power, data storage and data access capacity. Here we review recent developments of our laboratory, including progress in the chemical universe databases (GDB) and the fragment subset FDB-17, tools for ligand-based virtual screening by nearest neighbor searches, such as our multi-fingerprint browser for the ZINC database to select purchasable screening compounds, and their application to discover potent and selective inhibitors for calcium channel TRPV6 and Aurora A kinase, the polypharmacology browser (PPB) for predicting off-target effects, and finally interactive 3D-chemical space visualization using our online tools WebDrugCS and WebMolCS. All resources described in this paper are available for public use at www.gdb.unibe.ch.

Chemical correction of pre-mRNA splicing defects associated with sequestration of muscleblind-like 1 protein by expanded r(CAG)-containing transcripts.

PubMed

Kumar, Amit; Parkesh, Raman; Sznajder, Lukasz J; Childs-Disney, Jessica L; Sobczak, Krzysztof; Disney, Matthew D

2012-03-16

Recently, it was reported that expanded r(CAG) triplet repeats (r(CAG)(exp)) associated with untreatable neurological diseases cause pre-mRNA mis-splicing likely due to sequestration of muscleblind-like 1 (MBNL1) splicing factor. Bioactive small molecules that bind the 5'CAG/3'GAC motif found in r(CAG)(exp) hairpin structure were identified by using RNA binding studies and virtual screening/chemical similarity searching. Specifically, a benzylguanidine-containing small molecule was found to improve pre-mRNA alternative splicing of MBNL1-sensitive exons in cells expressing the toxic r(CAG)(exp). The compound was identified by first studying the binding of RNA 1 × 1 nucleotide internal loops to small molecules known to have affinity for nucleic acids. Those studies identified 4',6-diamidino-2-phenylindole (DAPI) as a specific binder to RNAs with the 5'CAG/3'GAC motif. DAPI was then used as a query molecule in a shape- and chemistry alignment-based virtual screen to identify compounds with improved properties, which identified 4-guanidinophenyl 4-guanidinobenzoate, a small molecule that improves pre-mRNA splicing defects associated with the r(CAG)(exp)-MBNL1 complex. This compound may facilitate the development of therapeutics to treat diseases caused by r(CAG)(exp) and could serve as a useful chemical tool to dissect the mechanisms of r(CAG)(exp) toxicity. The approach used in these studies, defining the small RNA motifs that bind small molecules with known affinity for nucleic acids and then using virtual screening to optimize them for bioactivity, may be generally applicable for designing small molecules that target other RNAs in the human genomic sequence.

Chemical correction of pre-mRNA splicing defects associated with sequestration of muscleblind-like 1 protein by expanded r(CAG) transcripts

PubMed Central

Kumar, Amit; Parkesh, Raman; Sznajder, Lukasz J.; Childs-Disney, Jessica; Sobczak, Krzysztof; Disney, Matthew D.

2012-01-01

Recently, it was reported that expanded r(CAG) triplet repeats (r(CAG)exp) associated with untreatable neurological diseases cause pre-mRNA mis-splicing likely due to sequestration of muscleblind-like 1 (MBNL1) splicing factor. Bioactive small molecules that bind the 5’CAG/3’GAC motif found in r(CAG)exp hairpin structure were identified by using RNA binding studies and virtual screening/chemical similarity searching. Specifically, a benzylguanidine-containing small molecule was found to improve pre-mRNA alternative splicing of MBNL1-sensitive exons in cells expressing the toxic r(CAG)exp. The compound was identified by first studying the binding of RNA 1×1 nucleotide internal loops to small molecules known to have affinity for nucleic acids. Those studies identified 4',6-diamidino-2-phenylindole (DAPI) as a specific binder to RNAs with the 5’CAG/3’GAC motif. DAPI was then used as a query molecule in a shape- and chemistry alignment-based virtual screen to identify compounds with improved properties, which identified 4-guanidinophenyl 4-guanidinobenzoate as small molecule capable of improving pre-mRNA splicing defects associated with the r(CAG)exp-MBNL1 complex. This compound may facilitate the development of therapeutics to treat diseases caused by r(CAG)exp and could serve as a useful chemical tool to dissect the mechanisms of r(CAG)exp toxicity. The approach used in these studies, defining the small RNA motifs that bind known nucleic acid binders and then using virtual screening to optimize them for bioactivity, may be generally applicable for designing small molecules that target other RNAs in human genomic sequence. PMID:22252896

Iowa Gambling Task with non-clinical participants: effects of using real + virtual cards and additional trials

PubMed Central

Overman, William H.; Pierce, Allison

2013-01-01

Performance on the Iowa Gambling Task (IGT) in clinical populations can be interpreted only in relation to established baseline performance in normal populations. As in all comparisons of assessment tools, the normal baseline must reflect performance under conditions in which subjects can function at their best levels. In this review, we show that a number of variables enhance IGT performance in non-clinical participants. First, optimal performance is produced by having participants turn over real cards while viewing virtual cards on a computer screen. The use of only virtual cards results in significantly lower performance than the combination of real + virtual cards. Secondly, administration of more than 100 trials also enhances performance. When using the real/virtual card procedure, performance is shown to significantly increase from early adolescence through young adulthood. Under these conditions young (mean age 19 years) and older (mean age 59 years) adults perform equally. Females, as a group, score lower than males because females tend to choose cards from high-frequency-of-gain Deck B. Groups of females with high or low gonadal hormones perform equally. Concurrent tasks, e.g., presentation of aromas, decrease performance in males. Age and gender effects are discussed in terms of a dynamic between testosterone and orbital prefrontal cortex. PMID:24376431

Missing depth cues in virtual reality limit performance and quality of three dimensional reaching movements

PubMed Central

Mayo, Johnathan; Baur, Kilian; Wittmann, Frieder; Riener, Robert; Wolf, Peter

2018-01-01

Background Goal-directed reaching for real-world objects by humans is enabled through visual depth cues. In virtual environments, the number and quality of available visual depth cues is limited, which may affect reaching performance and quality of reaching movements. Methods We assessed three-dimensional reaching movements in five experimental groups each with ten healthy volunteers. Three groups used a two-dimensional computer screen and two groups used a head-mounted display. The first screen group received the typically recreated visual depth cues, such as aerial and linear perspective, occlusion, shadows, and texture gradients. The second screen group received an abstract minimal rendering lacking those. The third screen group received the cues of the first screen group and absolute depth cues enabled by retinal image size of a known object, which realized with visual renderings of the handheld device and a ghost handheld at the target location. The two head-mounted display groups received the same virtually recreated visual depth cues as the second or the third screen group respectively. Additionally, they could rely on stereopsis and motion parallax due to head-movements. Results and conclusion All groups using the screen performed significantly worse than both groups using the head-mounted display in terms of completion time normalized by the straight-line distance to the target. Both groups using the head-mounted display achieved the optimal minimum in number of speed peaks and in hand path ratio, indicating that our subjects performed natural movements when using a head-mounted display. Virtually recreated visual depth cues had a minor impact on reaching performance. Only the screen group with rendered handhelds could outperform the other screen groups. Thus, if reaching performance in virtual environments is in the main scope of a study, we suggest applying a head-mounted display. Otherwise, when two-dimensional screens are used, achievable performance is likely limited by the reduced depth perception and not just by subjects’ motor skills. PMID:29293512

Synergism of virtual screening and medicinal chemistry: identification and optimization of allosteric antagonists of metabotropic glutamate receptor 1.

PubMed

Noeske, Tobias; Trifanova, Dina; Kauss, Valerjans; Renner, Steffen; Parsons, Christopher G; Schneider, Gisbert; Weil, Tanja

2009-08-01

We report the identification of novel potent and selective metabotropic glutamate receptor 1 (mGluR1) antagonists by virtual screening and subsequent hit optimization. For ligand-based virtual screening, molecules were represented by a topological pharmacophore descriptor (CATS-2D) and clustered by a self-organizing map (SOM). The most promising compounds were tested in mGluR1 functional and binding assays. We identified a potent chemotype exhibiting selective antagonistic activity at mGluR1 (functional IC(50)=0.74+/-0.29 microM). Hit optimization yielded lead structure 16 with an affinity of K(i)=0.024+/-0.001 microM and greater than 1000-fold selectivity for mGluR1 versus mGluR5. Homology-based receptor modelling suggests a binding site compatible with previously reported mutation studies. Our study demonstrates the usefulness of ligand-based virtual screening for scaffold-hopping and rapid lead structure identification in early drug discovery projects.

Performance on naturalistic virtual reality tasks depends on global cognitive functioning as assessed via traditional neurocognitive tests.

PubMed

Oliveira, Jorge; Gamito, Pedro; Alghazzawi, Daniyal M; Fardoun, Habib M; Rosa, Pedro J; Sousa, Tatiana; Picareli, Luís Felipe; Morais, Diogo; Lopes, Paulo

2017-08-14

This investigation sought to understand whether performance in naturalistic virtual reality tasks for cognitive assessment relates to the cognitive domains that are supposed to be measured. The Shoe Closet Test (SCT) was developed based on a simple visual search task involving attention skills, in which participants have to match each pair of shoes with the colors of the compartments in a virtual shoe closet. The interaction within the virtual environment was made using the Microsoft Kinect. The measures consisted of concurrent paper-and-pencil neurocognitive tests for global cognitive functioning, executive functions, attention, psychomotor ability, and the outcomes of the SCT. The results showed that the SCT correlated with global cognitive performance as measured with the Montreal Cognitive Assessment (MoCA). The SCT explained one third of the total variance of this test and revealed good sensitivity and specificity in discriminating scores below one standard deviation in this screening tool. These findings suggest that performance of such functional tasks involves a broad range of cognitive processes that are associated with global cognitive functioning and that may be difficult to isolate through paper-and-pencil neurocognitive tests.

Selection, application, and validation of a set of molecular descriptors for nuclear receptor ligands.

PubMed

Stewart, Eugene L; Brown, Peter J; Bentley, James A; Willson, Timothy M

2004-08-01

A methodology for the selection and validation of nuclear receptor ligand chemical descriptors is described. After descriptors for a targeted chemical space were selected, a virtual screening methodology utilizing this space was formulated for the identification of potential NR ligands from our corporate collection. Using simple descriptors and our virtual screening method, we are able to quickly identify potential NR ligands from a large collection of compounds. As validation of the virtual screening procedure, an 8, 000-membered NR targeted set and a 24, 000-membered diverse control set of compounds were selected from our in-house general screening collection and screened in parallel across a number of orphan NR FRET assays. For the two assays that provided at least one hit per set by the established minimum pEC(50) for activity, the results showed a 2-fold increase in the hit-rate of the targeted compound set over the diverse set.

A large scale virtual screen of DprE1.

PubMed

Wilsey, Claire; Gurka, Jessica; Toth, David; Franco, Jimmy

2013-12-01

Tuberculosis continues to plague the world with the World Health Organization estimating that about one third of the world's population is infected. Due to the emergence of MDR and XDR strains of TB, the need for novel therapeutics has become increasing urgent. Herein we report the results of a virtual screen of 4.1 million compounds against a promising drug target, DrpE1. The virtual compounds were obtained from the Zinc docking site and screened using the molecular docking program, AutoDock Vina. The computational hits have led to the identification of several promising lead compounds. Copyright © 2013 Elsevier Ltd. All rights reserved.

Multilevel Parallelization of AutoDock 4.2.

PubMed

Norgan, Andrew P; Coffman, Paul K; Kocher, Jean-Pierre A; Katzmann, David J; Sosa, Carlos P

2011-04-28

Virtual (computational) screening is an increasingly important tool for drug discovery. AutoDock is a popular open-source application for performing molecular docking, the prediction of ligand-receptor interactions. AutoDock is a serial application, though several previous efforts have parallelized various aspects of the program. In this paper, we report on a multi-level parallelization of AutoDock 4.2 (mpAD4). Using MPI and OpenMP, AutoDock 4.2 was parallelized for use on MPI-enabled systems and to multithread the execution of individual docking jobs. In addition, code was implemented to reduce input/output (I/O) traffic by reusing grid maps at each node from docking to docking. Performance of mpAD4 was examined on two multiprocessor computers. Using MPI with OpenMP multithreading, mpAD4 scales with near linearity on the multiprocessor systems tested. In situations where I/O is limiting, reuse of grid maps reduces both system I/O and overall screening time. Multithreading of AutoDock's Lamarkian Genetic Algorithm with OpenMP increases the speed of execution of individual docking jobs, and when combined with MPI parallelization can significantly reduce the execution time of virtual screens. This work is significant in that mpAD4 speeds the execution of certain molecular docking workloads and allows the user to optimize the degree of system-level (MPI) and node-level (OpenMP) parallelization to best fit both workloads and computational resources.

Ligand- and structure-based in silico studies to identify kinesin spindle protein (KSP) inhibitors as potential anticancer agents.

PubMed

Balakumar, Chandrasekaran; Ramesh, Muthusamy; Tham, Chuin Lean; Khathi, Samukelisiwe Pretty; Kozielski, Frank; Srinivasulu, Cherukupalli; Hampannavar, Girish A; Sayyad, Nisar; Soliman, Mahmoud E; Karpoormath, Rajshekhar

2017-11-29

Kinesin spindle protein (KSP) belongs to the kinesin superfamily of microtubule-based motor proteins. KSP is responsible for the establishment of the bipolar mitotic spindle which mediates cell division. Inhibition of KSP expedites the blockade of the normal cell cycle during mitosis through the generation of monoastral MT arrays that finally cause apoptotic cell death. As KSP is highly expressed in proliferating/cancer cells, it has gained considerable attention as a potential drug target for cancer chemotherapy. Therefore, this study envisaged to design novel KSP inhibitors by employing computational techniques/tools such as pharmacophore modelling, virtual database screening, molecular docking and molecular dynamics. Initially, the pharmacophore models were generated from the data-set of highly potent KSP inhibitors and the pharmacophore models were validated against in house test set ligands. The validated pharmacophore model was then taken for database screening (Maybridge and ChemBridge) to yield hits, which were further filtered for their drug-likeliness. The potential hits retrieved from virtual database screening were docked using CDOCKER to identify the ligand binding landscape. The top-ranked hits obtained from molecular docking were progressed to molecular dynamics (AMBER) simulations to deduce the ligand binding affinity. This study identified MB-41570 and CB-10358 as potential hits and evaluated these experimentally using in vitro KSP ATPase inhibition assays.

LIGSIFT: an open-source tool for ligand structural alignment and virtual screening.

PubMed

Roy, Ambrish; Skolnick, Jeffrey

2015-02-15

Shape-based alignment of small molecules is a widely used approach in computer-aided drug discovery. Most shape-based ligand structure alignment applications, both commercial and freely available ones, use the Tanimoto coefficient or similar functions for evaluating molecular similarity. Major drawbacks of using such functions are the size dependence of the score and the fact that the statistical significance of the molecular match using such metrics is not reported. We describe a new open-source ligand structure alignment and virtual screening (VS) algorithm, LIGSIFT, that uses Gaussian molecular shape overlay for fast small molecule alignment and a size-independent scoring function for efficient VS based on the statistical significance of the score. LIGSIFT was tested against the compounds for 40 protein targets available in the Directory of Useful Decoys and the performance was evaluated using the area under the ROC curve (AUC), the Enrichment Factor (EF) and Hit Rate (HR). LIGSIFT-based VS shows an average AUC of 0.79, average EF values of 20.8 and a HR of 59% in the top 1% of the screened library. LIGSIFT software, including the source code, is freely available to academic users at http://cssb.biology.gatech.edu/LIGSIFT. Supplementary data are available at Bioinformatics online. skolnick@gatech.edu. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Constructing and Validating High-Performance MIEC-SVM Models in Virtual Screening for Kinases: A Better Way for Actives Discovery

PubMed Central

Sun, Huiyong; Pan, Peichen; Tian, Sheng; Xu, Lei; Kong, Xiaotian; Li, Youyong; Dan Li; Hou, Tingjun

2016-01-01

The MIEC-SVM approach, which combines molecular interaction energy components (MIEC) derived from free energy decomposition and support vector machine (SVM), has been found effective in capturing the energetic patterns of protein-peptide recognition. However, the performance of this approach in identifying small molecule inhibitors of drug targets has not been well assessed and validated by experiments. Thereafter, by combining different model construction protocols, the issues related to developing best MIEC-SVM models were firstly discussed upon three kinase targets (ABL, ALK, and BRAF). As for the investigated targets, the optimized MIEC-SVM models performed much better than the models based on the default SVM parameters and Autodock for the tested datasets. Then, the proposed strategy was utilized to screen the Specs database for discovering potential inhibitors of the ALK kinase. The experimental results showed that the optimized MIEC-SVM model, which identified 7 actives with IC50 < 10 μM from 50 purchased compounds (namely hit rate of 14%, and 4 in nM level) and performed much better than Autodock (3 actives with IC50 < 10 μM from 50 purchased compounds, namely hit rate of 6%, and 2 in nM level), suggesting that the proposed strategy is a powerful tool in structure-based virtual screening. PMID:27102549

Constructing and Validating High-Performance MIEC-SVM Models in Virtual Screening for Kinases: A Better Way for Actives Discovery.

PubMed

Sun, Huiyong; Pan, Peichen; Tian, Sheng; Xu, Lei; Kong, Xiaotian; Li, Youyong; Dan Li; Hou, Tingjun

2016-04-22

The MIEC-SVM approach, which combines molecular interaction energy components (MIEC) derived from free energy decomposition and support vector machine (SVM), has been found effective in capturing the energetic patterns of protein-peptide recognition. However, the performance of this approach in identifying small molecule inhibitors of drug targets has not been well assessed and validated by experiments. Thereafter, by combining different model construction protocols, the issues related to developing best MIEC-SVM models were firstly discussed upon three kinase targets (ABL, ALK, and BRAF). As for the investigated targets, the optimized MIEC-SVM models performed much better than the models based on the default SVM parameters and Autodock for the tested datasets. Then, the proposed strategy was utilized to screen the Specs database for discovering potential inhibitors of the ALK kinase. The experimental results showed that the optimized MIEC-SVM model, which identified 7 actives with IC50 < 10 μM from 50 purchased compounds (namely hit rate of 14%, and 4 in nM level) and performed much better than Autodock (3 actives with IC50 < 10 μM from 50 purchased compounds, namely hit rate of 6%, and 2 in nM level), suggesting that the proposed strategy is a powerful tool in structure-based virtual screening.

Cognitive evaluation for the diagnosis of Alzheimer's disease based on Turing Test and Virtual Environments.

PubMed

Fernandez Montenegro, Juan Manuel; Argyriou, Vasileios

2017-05-01

Alzheimer's screening tests are commonly used by doctors to diagnose the patient's condition and stage as early as possible. Most of these tests are based on pen-paper interaction and do not embrace the advantages provided by new technologies. This paper proposes novel Alzheimer's screening tests based on virtual environments and game principles using new immersive technologies combined with advanced Human Computer Interaction (HCI) systems. These new tests are focused on the immersion of the patient in a virtual room, in order to mislead and deceive the patient's mind. In addition, we propose two novel variations of Turing Test proposed by Alan Turing as a method to detect dementia. As a result, four tests are introduced demonstrating the wide range of screening mechanisms that could be designed using virtual environments and game concepts. The proposed tests are focused on the evaluation of memory loss related to common objects, recent conversations and events; the diagnosis of problems in expressing and understanding language; the ability to recognize abnormalities; and to differentiate between virtual worlds and reality, or humans and machines. The proposed screening tests were evaluated and tested using both patients and healthy adults in a comparative study with state-of-the-art Alzheimer's screening tests. The results show the capacity of the new tests to distinguish healthy people from Alzheimer's patients. Copyright © 2017. Published by Elsevier Inc.

Identifying Novel Molecular Structures for Advanced Melanoma by Ligand-Based Virtual Screening

PubMed Central

Wang, Zhao; Lu, Yan; Seibel, William; Miller, Duane D.; Li, Wei

2009-01-01

We recently discovered a new class of thiazole analogs that are highly potent against melanoma cells. To expand the structure-activity relationship study and to explore potential new molecular scaffolds, we performed extensive ligand-based virtual screening against a compound library containing 342,910 small molecules. Two different approaches of virtual screening were carried out using the structure of our lead molecule: 1) connectivity-based search using Scitegic Pipeline Pilot from Accelerys and 2) molecular shape similarity search using Schrodinger software. Using a testing compound library, both approaches can rank similar compounds very high and rank dissimilar compounds very low, thus validating our screening methods. Structures identified from these searches were analyzed, and selected compounds were tested in vitro to assess their activity against melanoma cancer cell lines. Several molecules showed good anticancer activity. While none of the identified compounds showed better activity than our lead compound, they provided important insight into structural modifications for our lead compound and also provided novel platforms on which we can optimize new classes of anticancer compounds. One of the newly synthesized analogs based on this virtual screening has improved potency and selectivity against melanoma. PMID:19445498

CycloPs: generating virtual libraries of cyclized and constrained peptides including nonnatural amino acids.

PubMed

Duffy, Fergal J; Verniere, Mélanie; Devocelle, Marc; Bernard, Elise; Shields, Denis C; Chubb, Anthony J

2011-04-25

We introduce CycloPs, software for the generation of virtual libraries of constrained peptides including natural and nonnatural commercially available amino acids. The software is written in the cross-platform Python programming language, and features include generating virtual libraries in one-dimensional SMILES and three-dimensional SDF formats, suitable for virtual screening. The stand-alone software is capable of filtering the virtual libraries using empirical measurements, including peptide synthesizability by standard peptide synthesis techniques, stability, and the druglike properties of the peptide. The software and accompanying Web interface is designed to enable the rapid generation of large, structurally diverse, synthesizable virtual libraries of constrained peptides quickly and conveniently, for use in virtual screening experiments. The stand-alone software, and the Web interface for evaluating these empirical properties of a single peptide, are available at http://bioware.ucd.ie .

The effect of degree of immersion upon learning performance in virtual reality simulations for medical education.

PubMed

Gutiérrez, Fátima; Pierce, Jennifer; Vergara, Víctor M; Coulter, Robert; Saland, Linda; Caudell, Thomas P; Goldsmith, Timothy E; Alverson, Dale C

2007-01-01

Simulations are being used in education and training to enhance understanding, improve performance, and assess competence. However, it is important to measure the performance of these simulations as learning and training tools. This study examined and compared knowledge acquisition using a knowledge structure design. The subjects were first-year medical students at The University of New Mexico School of Medicine. One group used a fully immersed virtual reality (VR) environment using a head mounted display (HMD) and another group used a partially immersed (computer screen) VR environment. The study aims were to determine whether there were significant differences between the two groups as measured by changes in knowledge structure before and after the VR simulation experience. The results showed that both groups benefited from the VR simulation training as measured by the significant increased similarity to the expert knowledge network after the training experience. However, the immersed group showed a significantly higher gain than the partially immersed group. This study demonstrated a positive effect of VR simulation on learning as reflected by improvements in knowledge structure but an enhanced effect of full-immersion using a HMD vs. a screen-based VR system.

Virtual screening using the ligand ZINC database for novel lipoxygenase-3 inhibitors.

PubMed

Monika; Kour, Janmeet; Singh, Kulwinder

2013-01-01

The leukotrienes constitute a group of arachidonic acid-derived compounds with biologic activities suggesting important roles in inflammation and immediate hypersensitivity. Epidermis-type lipoxygenase-3 (ALOXE3), a distinct subclass within the multigene family of mammalian lipoxygenases, is a novel isoenzyme involved in the metabolism of leukotrienes and plays a very important role in skin barrier functions. Lipoxygenase selective inhibitors such as azelastine and zileuton are currently used to reduce inflammatory response. Nausea, pharyngolaryngeal pain, headache, nasal burning and somnolence are the most frequently reported adverse effects of these drugs. Therefore, there is still a need to develop more potent lipoxygenase inhibitors. In this paper, we report the screening of various compounds from the ZINC database (contains over 21 million compounds) using the Molegro Virtual Docker software against the ALOXE3 protein. Screening was performed using molecular constraints tool to filter compounds with physico-chemical properties similar to the 1N8Q bound ligand protocatechuic acid. The analysis resulted in 4319 Lipinski compliant hits which are docked and scored to identify structurally novel ligands that make similar interactions to those of known ligands or may have different interactions with other parts of the binding site. Our screening approach identified four molecules ZINC84299674; ZINC76643455; ZINC84299122 & ZINC75626957 with MolDock score of -128.901, -120.22, -116.873 & - 102.116 kcal/mol, respectively. Their energy scores were better than the 1N8Q bound co-crystallized ligand protocatechuic acid (with MolDock score of -77.225 kcal/mol). All the ligands were docked within the binding pocket forming interactions with amino acid residues.

Using mHealth technologies to improve the identification of behavioral health problems in urban primary care settings.

PubMed

Staeheli, Martha; Aseltine, Robert H; Schilling, Elizabeth; Anderson, Daren; Gould, Bruce

2017-01-01

Behavioral health disorders remain under recognized and under diagnosed among urban primary care patients. Screening patients for such problems is widely recommended, yet is challenging to do in a brief primary care encounter, particularly for this socially and medically complex patient population. In 2013, intervention patients at an urban Connecticut primary clinic were screened for post-traumatic stress disorder, depression, and risky drinking (n = 146) using an electronic tablet-based screening tool. Screening data were compared to electronic health record data from control patients (n = 129) to assess differences in the prevalence of behavioral health problems, rates of follow-up care, and the rate of newly identified cases in the intervention group. Results from logistic regressions indicated that both groups had similar rates of disorder at baseline. Patients in the intervention group were five times more likely to be identified with depression (p < 0.05). Post-traumatic stress disorder was virtually unrecognized among controls but was observed in 23% of the intervention group (p < 0.001). The vast majority of behavioral health problems identified in the intervention group were new cases. Follow-up rates were significantly higher in the intervention group relative to controls, but were low overall. This tablet-based electronic screening tool identified significantly higher rates of behavioral health disorders than have been previously reported for this patient population. Electronic risk screening using patient-reported outcome measures offers an efficient approach to improving the identification of behavioral health problems and improving rates of follow-up care.

Applications of self-organizing neural networks in virtual screening and diversity selection.

PubMed

Selzer, Paul; Ertl, Peter

2006-01-01

Artificial neural networks provide a powerful technique for the analysis and modeling of nonlinear relationships between molecular structures and pharmacological activity. Many network types, including Kohonen and counterpropagation, also provide an intuitive method for the visual assessment of correspondence between the input and output data. This work shows how a combination of neural networks and radial distribution function molecular descriptors can be applied in various areas of industrial pharmaceutical research. These applications include the prediction of biological activity, the selection of screening candidates (cherry picking), and the extraction of representative subsets from large compound collections such as combinatorial libraries. The methods described have also been implemented as an easy-to-use Web tool, allowing chemists to perform interactive neural network experiments on the Novartis intranet.

Virtual screening of cocrystal formers for CL-20

NASA Astrophysics Data System (ADS)

Zhou, Jun-Hong; Chen, Min-Bo; Chen, Wei-Ming; Shi, Liang-Wei; Zhang, Chao-Yang; Li, Hong-Zhen

2014-08-01

According to the structure characteristics of 2,4,6,8,10,12-hexanitrohexaazaisowurtzitane (CL-20) and the kinetic mechanism of the cocrystal formation, the method of virtual screening CL-20 cocrystal formers by the criterion of the strongest intermolecular site pairing energy (ISPE) was proposed. In this method the strongest ISPE was thought to determine the first step of the cocrystal formation. The prediction results for four sets of common drug molecule cocrystals by this method were compared with those by the total ISPE method from the reference (Musumeci et al., 2011), and the experimental results. This method was then applied to virtually screen the CL-20 cocrystal formers, and the prediction results were compared with the experimental results.

Virtual Screening of Receptor Sites for Molecularly Imprinted Polymers.

PubMed

Bates, Ferdia; Cela-Pérez, María Concepción; Karim, Kal; Piletsky, Sergey; López-Vilariño, José Manuel

2016-08-01

Molecularly Imprinted Polymers (MIPs) are highly advantageous in the field of analytical chemistry. However, interference from secondary molecules can also impede capture of a target by a MIP receptor. This greatly complicates the design process and often requires extensive laboratory screening which is time consuming, costly, and creates substantial waste products. Herein, is presented a new technique for screening of "virtually imprinted receptors" for rebinding of the molecular template as well as secondary structures, correlating the virtual predictions with experimentally acquired data in three case studies. This novel technique is particularly applicable to the evaluation and prediction of MIP receptor specificity and efficiency in complex aqueous systems. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hit identification and optimization in virtual screening: practical recommendations based on a critical literature analysis.

PubMed

Zhu, Tian; Cao, Shuyi; Su, Pin-Chih; Patel, Ram; Shah, Darshan; Chokshi, Heta B; Szukala, Richard; Johnson, Michael E; Hevener, Kirk E

2013-09-12

A critical analysis of virtual screening results published between 2007 and 2011 was performed. The activity of reported hit compounds from over 400 studies was compared to their hit identification criteria. Hit rates and ligand efficiencies were calculated to assist in these analyses, and the results were compared with factors such as the size of the virtual library and the number of compounds tested. A series of promiscuity, druglike, and ADMET filters were applied to the reported hits to assess the quality of compounds reported, and a careful analysis of a subset of the studies that presented hit optimization was performed. These data allowed us to make several practical recommendations with respect to selection of compounds for experimental testing, definition of hit identification criteria, and general virtual screening hit criteria to allow for realistic hit optimization. A key recommendation is the use of size-targeted ligand efficiency values as hit identification criteria.

Discovery of covalent inhibitors for MIF tautomerase via cocrystal structures with phantom hits from virtual screening

DOE Office of Scientific and Technical Information (OSTI.GOV)

McLean, Larry R.; Zhang, Ying; Li, Hua

Biochemical and X-ray crystallographic studies confirmed that hydroxyquinoline derivatives identified by virtual screening were actually covalent inhibitors of the MIF tautomerase. Adducts were formed by N-alkylation of the Pro-1 at the catalytic site with a loss of an amino group of the inhibitor.

Virtual screening and pharmacophore design for a novel theoretical inhibitor of macrophage stimulating factor as a metastatic agent.

PubMed

Torktaz, Ibrahim; Mohamadhashem, Faezeh; Esmaeili, Abolghasem; Behjati, Mohaddeseh; Sharifzadeh, Sara

2013-01-01

Metastasis is a crucial aspect of cancer. Macrophage stimulating protein (MSP) is a single chain protein and can be cleaved by serum proteases. MSP has several roles in metastasis. In this in silico study, MSP as a metastatic agent was considered as a drug target. Crystallographic structure of MSP was retrieved from protein data bank. To find a chemical inhibitor of MSP, a library of KEGG compounds was screened and 1000 shape complemented ligands were retrieved with FindSite algorithm. Molegro Virtual Docker (MVD) software was used for docking simulation of shape complemented ligands against MSP. Moldock score was used as scoring function for virtual screening and potential inhibitors with more negative binding energy were obtained. PLANS scoring function was used for revaluation of virtual screening data. The top found chemical had binding affinity of -183.55 based on MolDock score and equal to -66.733 PLANTs score to MSP structure. Based on pharmacophore model of potential inhibitor, this study suggests that the chemical which was found in this research and its derivate can be used for subsequent laboratory studies.

Virtual Ligand Screening Using PL-PatchSurfer2, a Molecular Surface-Based Protein-Ligand Docking Method.

PubMed

Shin, Woong-Hee; Kihara, Daisuke

2018-01-01

Virtual screening is a computational technique for predicting a potent binding compound for a receptor protein from a ligand library. It has been a widely used in the drug discovery field to reduce the efforts of medicinal chemists to find hit compounds by experiments.Here, we introduce our novel structure-based virtual screening program, PL-PatchSurfer, which uses molecular surface representation with the three-dimensional Zernike descriptors, which is an effective mathematical representation for identifying physicochemical complementarities between local surfaces of a target protein and a ligand. The advantage of the surface-patch description is its tolerance on a receptor and compound structure variation. PL-PatchSurfer2 achieves higher accuracy on apo form and computationally modeled receptor structures than conventional structure-based virtual screening programs. Thus, PL-PatchSurfer2 opens up an opportunity for targets that do not have their crystal structures. The program is provided as a stand-alone program at http://kiharalab.org/plps2 . We also provide files for two ligand libraries, ChEMBL and ZINC Drug-like.

Virtual Steel Connection Sculpture--Student Learning Assessment

ERIC Educational Resources Information Center

Chou, Karen C.; Moaveni, Saeed; Drane, Denise

2016-01-01

A Virtual Steel Connection Sculpture was developed through a grant from the National Science Foundation. The Virtual Sculpture is an interactive tool that shows students and anyone interested in connections how steel members are connected. This tool is created to complement students' steel design courses. The features of this educational tool,…

The Virtual Intercultural Team Tool

ERIC Educational Resources Information Center

Rus, Calin

2010-01-01

This article describes the Virtual Intercultural Team Tool (VITT) and discusses its processes and benefits. VIIT is a virtual platform designed with the aim of assisting European project teams to improve intercultural communication and build on their cultural diversity for effective implementation of their projects. It is a process-focused tool,…

Integrated Data Visualization and Virtual Reality Tool

NASA Technical Reports Server (NTRS)

Dryer, David A.

1998-01-01

The Integrated Data Visualization and Virtual Reality Tool (IDVVRT) Phase II effort was for the design and development of an innovative Data Visualization Environment Tool (DVET) for NASA engineers and scientists, enabling them to visualize complex multidimensional and multivariate data in a virtual environment. The objectives of the project were to: (1) demonstrate the transfer and manipulation of standard engineering data in a virtual world; (2) demonstrate the effects of design and changes using finite element analysis tools; and (3) determine the training and engineering design and analysis effectiveness of the visualization system.

Large-scale virtual screening on public cloud resources with Apache Spark.

PubMed

Capuccini, Marco; Ahmed, Laeeq; Schaal, Wesley; Laure, Erwin; Spjuth, Ola

2017-01-01

Structure-based virtual screening is an in-silico method to screen a target receptor against a virtual molecular library. Applying docking-based screening to large molecular libraries can be computationally expensive, however it constitutes a trivially parallelizable task. Most of the available parallel implementations are based on message passing interface, relying on low failure rate hardware and fast network connection. Google's MapReduce revolutionized large-scale analysis, enabling the processing of massive datasets on commodity hardware and cloud resources, providing transparent scalability and fault tolerance at the software level. Open source implementations of MapReduce include Apache Hadoop and the more recent Apache Spark. We developed a method to run existing docking-based screening software on distributed cloud resources, utilizing the MapReduce approach. We benchmarked our method, which is implemented in Apache Spark, docking a publicly available target receptor against [Formula: see text]2.2 M compounds. The performance experiments show a good parallel efficiency (87%) when running in a public cloud environment. Our method enables parallel Structure-based virtual screening on public cloud resources or commodity computer clusters. The degree of scalability that we achieve allows for trying out our method on relatively small libraries first and then to scale to larger libraries. Our implementation is named Spark-VS and it is freely available as open source from GitHub (https://github.com/mcapuccini/spark-vs).Graphical abstract.

Effects of 3D Virtual Simulators in the Introductory Wind Energy Course: A Tool for Teaching Engineering Concepts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Do, Phuong T.; Moreland, John R.; Delgado, Catherine

Our research provides an innovative solution for optimizing learning effectiveness and improving postsecondary education through the development of virtual simulators that can be easily used and integrated into existing wind energy curriculum. Two 3D virtual simulators are developed in our laboratory for use in an immersive 3D virtual reality (VR) system or for 3D display on a 2D screen. Our goal is to apply these prototypical simulators to train postsecondary students and professionals in wind energy education; and to offer experiential learning opportunities in 3D modeling, simulation, and visualization. The issue of transferring learned concepts to practical applications is amore » widespread problem in postsecondary education. Related to this issue is a critical demand to educate and train a generation of professionals for the wind energy industry. With initiatives such as the U.S. Department of Energy's “20% Wind Energy by 2030” outlining an exponential increase of wind energy capacity over the coming years, revolutionary educational reform is needed to meet the demand for education in the field of wind energy. These developments and implementation of Virtual Simulators and accompanying curriculum will propel national reforms, meeting the needs of the wind energy industrial movement and addressing broader educational issues that affect a number of disciplines.« less

Effects of 3D Virtual Simulators in the Introductory Wind Energy Course: A Tool for Teaching Engineering Concepts

DOE PAGES

Do, Phuong T.; Moreland, John R.; Delgado, Catherine; ...

2013-01-01

Our research provides an innovative solution for optimizing learning effectiveness and improving postsecondary education through the development of virtual simulators that can be easily used and integrated into existing wind energy curriculum. Two 3D virtual simulators are developed in our laboratory for use in an immersive 3D virtual reality (VR) system or for 3D display on a 2D screen. Our goal is to apply these prototypical simulators to train postsecondary students and professionals in wind energy education; and to offer experiential learning opportunities in 3D modeling, simulation, and visualization. The issue of transferring learned concepts to practical applications is amore » widespread problem in postsecondary education. Related to this issue is a critical demand to educate and train a generation of professionals for the wind energy industry. With initiatives such as the U.S. Department of Energy's “20% Wind Energy by 2030” outlining an exponential increase of wind energy capacity over the coming years, revolutionary educational reform is needed to meet the demand for education in the field of wind energy. These developments and implementation of Virtual Simulators and accompanying curriculum will propel national reforms, meeting the needs of the wind energy industrial movement and addressing broader educational issues that affect a number of disciplines.« less

Discovery of Novel Human Epidermal Growth Factor Receptor-2 Inhibitors by Structure-based Virtual Screening.

PubMed

Shi, Zheng; Yu, Tian; Sun, Rong; Wang, Shan; Chen, Xiao-Qian; Cheng, Li-Jia; Liu, Rong

2016-01-01

Human epidermal growth factor receptor-2 (HER2) is a trans-membrane receptor like protein, and aberrant signaling of HER2 is implicated in many human cancers, such as ovarian cancer, gastric cancer, and prostate cancer, most notably breast cancer. Moreover, it has been in the spotlight in the recent years as a promising new target for therapy of breast cancer. Since virtual screening has become an integral part of the drug discovery process, it is of great significant to identify novel HER2 inhibitors by structure-based virtual screening. In this study, we carried out a series of elegant bioinformatics approaches, such as virtual screening and molecular dynamics (MD) simulations to identify HER2 inhibitors from Food and Drug Administration-approved small molecule drug as potential "new use" drugs. Molecular docking identified top 10 potential drugs which showed spectrum affinity to HER2. Moreover, MD simulations suggested that ZINC08214629 (Nonoxynol-9) and ZINC03830276 (Benzonatate) might exert potential inhibitory effects against HER2-targeted anti-breast cancer therapeutics. Together, our findings may provide successful application of virtual screening studies in the lead discovery process, and suggest that our discovered small molecules could be effective HER2 inhibitor candidates for further study. A series of elegant bioinformatics approaches, including virtual screening and molecular dynamics (MD) simulations were took advantage to identify human epidermal growth factor receptor-2 (HER2) inhibitors. Molecular docking recognized top 10 candidate compounds, which showed spectrum affinity to HER2. Further, MD simulations suggested that ZINC08214629 (Nonoxynol-9) and ZINC03830276 (Benzonatate) in candidate compounds were identified as potential "new use" drugs against HER2-targeted anti-breast cancer therapeutics. Abbreviations used: HER2: Human epidermal growth factor receptor-2, FDA: Food and Drug Administration, PDB: Protein Database Bank, RMSDs: Root mean square deviations, SPC: Single point charge, PME: Particle mesh Ewald, NVT: Constant volume, NPT: Constant pressure, RMSF: Root-mean-square fluctuation.

Identification of promising DNA GyrB inhibitors for Tuberculosis using pharmacophore-based virtual screening, molecular docking and molecular dynamics studies.

PubMed

Islam, Md Ataul; Pillay, Tahir S

2017-08-01

In this study, we searched for potential DNA GyrB inhibitors using pharmacophore-based virtual screening followed by molecular docking and molecular dynamics simulation approaches. For this purpose, a set of 248 DNA GyrB inhibitors was collected from the literature and a well-validated pharmacophore model was generated. The best pharmacophore model explained that two each of hydrogen bond acceptors and hydrophobicity regions were critical for inhibition of DNA GyrB. Good statistical results of the pharmacophore model indicated that the model was robust in nature. Virtual screening of molecular databases revealed three molecules as potential antimycobacterial agents. The final screened promising compounds were evaluated in molecular docking and molecular dynamics simulation studies. In the molecular dynamics studies, RMSD and RMSF values undoubtedly explained that the screened compounds formed stable complexes with DNA GyrB. Therefore, it can be concluded that the compounds identified may have potential for the treatment of TB. © 2017 John Wiley & Sons A/S.

Improving Balance in TBI Using a Low-Cost Customized Virtual Reality Rehabilitation Tool

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-14-2-0150 TITLE: Improving Balance in TBI Using a Low-Cost Customized Virtual Reality Rehabilitation Tool PRINCIPAL...AND SUBTITLE Improving Balance in TBI Using a Low-Cost Customized Virtual Reality Rehabilitation Tool 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The proposed study will implement and evaluate a novel, low-cost, Virtual Reality (VR

Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein-ligand binding challenge

NASA Astrophysics Data System (ADS)

Perryman, Alexander L.; Santiago, Daniel N.; Forli, Stefano; Santos-Martins, Diogo; Olson, Arthur J.

2014-04-01

To rigorously assess the tools and protocols that can be used to understand and predict macromolecular recognition, and to gain more structural insight into three newly discovered allosteric binding sites on a critical drug target involved in the treatment of HIV infections, the Olson and Levy labs collaborated on the SAMPL4 challenge. This computational blind challenge involved predicting protein-ligand binding against the three allosteric sites of HIV integrase (IN), a viral enzyme for which two drugs (that target the active site) have been approved by the FDA. Positive control cross-docking experiments were utilized to select 13 receptor models out of an initial ensemble of 41 different crystal structures of HIV IN. These 13 models of the targets were selected using our new "Rank Difference Ratio" metric. The first stage of SAMPL4 involved using virtual screens to identify 62 active, allosteric IN inhibitors out of a set of 321 compounds. The second stage involved predicting the binding site(s) and crystallographic binding mode(s) for 57 of these inhibitors. Our team submitted four entries for the first stage that utilized: (1) AutoDock Vina (AD Vina) plus visual inspection; (2) a new common pharmacophore engine; (3) BEDAM replica exchange free energy simulations, and a Consensus approach that combined the predictions of all three strategies. Even with the SAMPL4's very challenging compound library that displayed a significantly lower amount of structural diversity than most libraries that are conventionally employed in prospective virtual screens, these approaches produced hit rates of 24, 25, 34, and 27 %, respectively, on a set with 19 % declared binders. Our only entry for the second stage challenge was based on the results of AD Vina plus visual inspection, and it ranked third place overall according to several different metrics provided by the SAMPL4 organizers. The successful results displayed by these approaches highlight the utility of the computational structure-based drug discovery tools and strategies that are being developed to advance the goals of the newly created, multi-institution, NIH-funded center called the "HIV Interaction and Viral Evolution Center".

Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein-ligand binding challenge.

PubMed

Perryman, Alexander L; Santiago, Daniel N; Forli, Stefano; Martins, Diogo Santos; Olson, Arthur J

2014-04-01

To rigorously assess the tools and protocols that can be used to understand and predict macromolecular recognition, and to gain more structural insight into three newly discovered allosteric binding sites on a critical drug target involved in the treatment of HIV infections, the Olson and Levy labs collaborated on the SAMPL4 challenge. This computational blind challenge involved predicting protein-ligand binding against the three allosteric sites of HIV integrase (IN), a viral enzyme for which two drugs (that target the active site) have been approved by the FDA. Positive control cross-docking experiments were utilized to select 13 receptor models out of an initial ensemble of 41 different crystal structures of HIV IN. These 13 models of the targets were selected using our new "Rank Difference Ratio" metric. The first stage of SAMPL4 involved using virtual screens to identify 62 active, allosteric IN inhibitors out of a set of 321 compounds. The second stage involved predicting the binding site(s) and crystallographic binding mode(s) for 57 of these inhibitors. Our team submitted four entries for the first stage that utilized: (1) AutoDock Vina (AD Vina) plus visual inspection; (2) a new common pharmacophore engine; (3) BEDAM replica exchange free energy simulations, and a Consensus approach that combined the predictions of all three strategies. Even with the SAMPL4's very challenging compound library that displayed a significantly lower amount of structural diversity than most libraries that are conventionally employed in prospective virtual screens, these approaches produced hit rates of 24, 25, 34, and 27 %, respectively, on a set with 19 % declared binders. Our only entry for the second stage challenge was based on the results of AD Vina plus visual inspection, and it ranked third place overall according to several different metrics provided by the SAMPL4 organizers. The successful results displayed by these approaches highlight the utility of the computational structure-based drug discovery tools and strategies that are being developed to advance the goals of the newly created, multi-institution, NIH-funded center called the "HIV Interaction and Viral Evolution Center".

Virtual screening and rational drug design method using structure generation system based on 3D-QSAR and docking.

PubMed

Chen, H F; Dong, X C; Zen, B S; Gao, K; Yuan, S G; Panaye, A; Doucet, J P; Fan, B T

2003-08-01

An efficient virtual and rational drug design method is presented. It combines virtual bioactive compound generation with 3D-QSAR model and docking. Using this method, it is possible to generate a lot of highly diverse molecules and find virtual active lead compounds. The method was validated by the study of a set of anti-tumor drugs. With the constraints of pharmacophore obtained by DISCO implemented in SYBYL 6.8, 97 virtual bioactive compounds were generated, and their anti-tumor activities were predicted by CoMFA. Eight structures with high activity were selected and screened by the 3D-QSAR model. The most active generated structure was further investigated by modifying its structure in order to increase the activity. A comparative docking study with telomeric receptor was carried out, and the results showed that the generated structures could form more stable complexes with receptor than the reference compound selected from experimental data. This investigation showed that the proposed method was a feasible way for rational drug design with high screening efficiency.

Impact of a Virtual Clinic in a Paediatric Cardiology Network on Northeast Brazil.

PubMed

de Araújo, Juliana Sousa Soares; Dias Filho, Adalberto Vieira; Silva Gomes, Renata Grigório; Regis, Cláudio Teixeira; Rodrigues, Klecida Nunes; Siqueira, Nicoly Negreiros; Albuquerque, Fernanda Cruz de Lira; Mourato, Felipe Alves; Mattos, Sandra da Silva

2015-01-01

Introduction. Congenital heart diseases (CHD) affect approximately 1% of live births and is an important cause of neonatal morbidity and mortality. Despite that, there is a shortage of paediatric cardiologists in Brazil, mainly in the northern and northeastern regions. In this context, the implementation of virtual outpatient clinics with the aid of different telemedicine resources may help in the care of children with heart defects. Methods. Patients under 18 years of age treated in virtual outpatient clinics between January 2013 and May 2014 were selected. They were divided into 2 groups: those who had and those who had not undergone a screening process for CHD in the neonatal period. Clinical and demographic characteristics were collected for further statistical analysis. Results. A total of 653 children and teenagers were treated in the virtual outpatient clinics. From these, 229 had undergone a neonatal screening process. Fewer abnormalities were observed on the physical examination of the screened patients. Conclusion. The implementation of pediatric cardiology virtual outpatient clinics can have a positive impact in the care provided to people in areas with lack of skilled professionals.

Identification of novel drug scaffolds for inhibition of SARS-CoV 3-Chymotrypsin-like protease using virtual and high-throughput screenings.

PubMed

Lee, Hyun; Mittal, Anuradha; Patel, Kavankumar; Gatuz, Joseph L; Truong, Lena; Torres, Jaime; Mulhearn, Debbie C; Johnson, Michael E

2014-01-01

We have used a combination of virtual screening (VS) and high-throughput screening (HTS) techniques to identify novel, non-peptidic small molecule inhibitors against human SARS-CoV 3CLpro. A structure-based VS approach integrating docking and pharmacophore based methods was employed to computationally screen 621,000 compounds from the ZINC library. The screening protocol was validated using known 3CLpro inhibitors and was optimized for speed, improved selectivity, and for accommodating receptor flexibility. Subsequently, a fluorescence-based enzymatic HTS assay was developed and optimized to experimentally screen approximately 41,000 compounds from four structurally diverse libraries chosen mainly based on the VS results. False positives from initial HTS hits were eliminated by a secondary orthogonal binding analysis using surface plasmon resonance (SPR). The campaign identified a reversible small molecule inhibitor exhibiting mixed-type inhibition with a K(i) value of 11.1 μM. Together, these results validate our protocols as suitable approaches to screen virtual and chemical libraries, and the newly identified compound reported in our study represents a promising structural scaffold to pursue for further SARS-CoV 3CLpro inhibitor development. Copyright © 2013. Published by Elsevier Ltd.

PyGOLD: a python based API for docking based virtual screening workflow generation.

PubMed

Patel, Hitesh; Brinkjost, Tobias; Koch, Oliver

2017-08-15

Molecular docking is one of the successful approaches in structure based discovery and development of bioactive molecules in chemical biology and medicinal chemistry. Due to the huge amount of computational time that is still required, docking is often the last step in a virtual screening approach. Such screenings are set as workflows spanned over many steps, each aiming at different filtering task. These workflows can be automatized in large parts using python based toolkits except for docking using the docking software GOLD. However, within an automated virtual screening workflow it is not feasible to use the GUI in between every step to change the GOLD configuration file. Thus, a python module called PyGOLD was developed, to parse, edit and write the GOLD configuration file and to automate docking based virtual screening workflows. The latest version of PyGOLD, its documentation and example scripts are available at: http://www.ccb.tu-dortmund.de/koch or http://www.agkoch.de. PyGOLD is implemented in Python and can be imported as a standard python module without any further dependencies. oliver.koch@agkoch.de, oliver.koch@tu-dortmund.de. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Virtual screening applications: a study of ligand-based methods and different structure representations in four different scenarios.

PubMed

Hristozov, Dimitar P; Oprea, Tudor I; Gasteiger, Johann

2007-01-01

Four different ligand-based virtual screening scenarios are studied: (1) prioritizing compounds for subsequent high-throughput screening (HTS); (2) selecting a predefined (small) number of potentially active compounds from a large chemical database; (3) assessing the probability that a given structure will exhibit a given activity; (4) selecting the most active structure(s) for a biological assay. Each of the four scenarios is exemplified by performing retrospective ligand-based virtual screening for eight different biological targets using two large databases--MDDR and WOMBAT. A comparison between the chemical spaces covered by these two databases is presented. The performance of two techniques for ligand--based virtual screening--similarity search with subsequent data fusion (SSDF) and novelty detection with Self-Organizing Maps (ndSOM) is investigated. Three different structure representations--2,048-dimensional Daylight fingerprints, topological autocorrelation weighted by atomic physicochemical properties (sigma electronegativity, polarizability, partial charge, and identity) and radial distribution functions weighted by the same atomic physicochemical properties--are compared. Both methods were found applicable in scenario one. The similarity search was found to perform slightly better in scenario two while the SOM novelty detection is preferred in scenario three. No method/descriptor combination achieved significant success in scenario four.

Discovery of new inhibitors of the bacterial peptidoglycan biosynthesis enzymes MurD and MurF by structure-based virtual screening.

PubMed

Turk, Samo; Kovac, Andreja; Boniface, Audrey; Bostock, Julieanne M; Chopra, Ian; Blanot, Didier; Gobec, Stanislav

2009-03-01

The ATP-dependent Mur ligases (MurC, MurD, MurE and MurF) successively add L-Ala, D-Glu, meso-A(2)pm or L-Lys, and D-Ala-D-Ala to the nucleotide precursor UDP-MurNAc, and they represent promising targets for antibacterial drug discovery. We have used the molecular docking programme eHiTS for the virtual screening of 1990 compounds from the National Cancer Institute 'Diversity Set' on MurD and MurF. The 50 top-scoring compounds from screening on each enzyme were selected for experimental biochemical evaluation. Our approach of virtual screening and subsequent in vitro biochemical evaluation of the best ranked compounds has provided four novel MurD inhibitors (best IC(50)=10 microM) and one novel MurF inhibitor (IC(50)=63 microM).

Identification of a New Isoindole-2-yl Scaffold as a Qo and Qi Dual Inhibitor of Cytochrome bc 1 Complex: Virtual Screening, Synthesis, and Biochemical Assay.

PubMed

Azizian, Homa; Bagherzadeh, Kowsar; Shahbazi, Sophia; Sharifi, Niusha; Amanlou, Massoud

2017-09-18

Respiratory chain ubiquinol-cytochrome (cyt) c oxidoreductase (cyt bc 1 or complex III) has been demonstrated as a promising target for numerous antibiotics and fungicide applications. In this study, a virtual screening of NCI diversity database was carried out in order to find novel Qo/Qi cyt bc 1 complex inhibitors. Structure-based virtual screening and molecular docking methodology were employed to further screen compounds with inhibition activity against cyt bc 1 complex after extensive reliability validation protocol with cross-docking method and identification of the best score functions. Subsequently, the application of rational filtering procedure over the target database resulted in the elucidation of a novel class of cyt bc 1 complex potent inhibitors with comparable binding energies and biological activities to those of the standard inhibitor, antimycin.

Poor Man's Virtual Camera: Real-Time Simultaneous Matting and Camera Pose Estimation.

PubMed

Szentandrasi, Istvan; Dubska, Marketa; Zacharias, Michal; Herout, Adam

2016-03-18

Today's film and advertisement production heavily uses computer graphics combined with living actors by chromakeying. The matchmoving process typically takes a considerable manual effort. Semi-automatic matchmoving tools exist as well, but they still work offline and require manual check-up and correction. In this article, we propose an instant matchmoving solution for green screen. It uses a recent technique of planar uniform marker fields. Our technique can be used in indie and professional filmmaking as a cheap and ultramobile virtual camera, and for shot prototyping and storyboard creation. The matchmoving technique based on marker fields of shades of green is very computationally efficient: we developed and present in the article a mobile application running at 33 FPS. Our technique is thus available to anyone with a smartphone at low cost and with easy setup, opening space for new levels of filmmakers' creative expression.

Thoracic, Lumbar, and Sacral Pedicle Screw Placement Using Stryker-Ziehm Virtual Screw Technology and Navigated Stryker Cordless Driver 3: Technical Note.

PubMed

Satarasinghe, Praveen; Hamilton, Kojo D; Tarver, Michael J; Buchanan, Robert J; Koltz, Michael T

2018-04-17

Utilization of pedicle screws (PS) for spine stabilization is common in spinal surgery. With reliance on visual inspection of anatomical landmarks prior to screw placement, the free-hand technique requires a high level of surgeon skill and precision. Three-dimensional (3D), computer-assisted virtual neuronavigation improves the precision of PS placement and minimization steps. Twenty-three patients with degenerative, traumatic, or neoplastic pathologies received treatment via a novel three-step PS technique that utilizes a navigated power driver in combination with virtual screw technology. (1) Following visualization of neuroanatomy using intraoperative CT, a navigated 3-mm match stick drill bit was inserted at an anatomical entry point with a screen projection showing a virtual screw. (2) A Navigated Stryker Cordless Driver with an appropriate tap was used to access the vertebral body through a pedicle with a screen projection again showing a virtual screw. (3) A Navigated Stryker Cordless Driver with an actual screw was used with a screen projection showing the same virtual screw. One hundred and forty-four consecutive screws were inserted using this three-step, navigated driver, virtual screw technique. Only 1 screw needed intraoperative revision after insertion using the three-step, navigated driver, virtual PS technique. This amounts to a 0.69% revision rate. One hundred percent of patients had intraoperative CT reconstructed images taken to confirm hardware placement. Pedicle screw placement utilizing the Stryker-Ziehm neuronavigation virtual screw technology with a three step, navigated power drill technique is safe and effective.

Ligand.Info small-molecule Meta-Database.

PubMed

von Grotthuss, Marcin; Koczyk, Grzegorz; Pas, Jakub; Wyrwicz, Lucjan S; Rychlewski, Leszek

2004-12-01

Ligand.Info is a compilation of various publicly available databases of small molecules. The total size of the Meta-Database is over 1 million entries. The compound records contain calculated three-dimensional coordinates and sometimes information about biological activity. Some molecules have information about FDA drug approving status or about anti-HIV activity. Meta-Database can be downloaded from the http://Ligand.Info web page. The database can also be screened using a Java-based tool. The tool can interactively cluster sets of molecules on the user side and automatically download similar molecules from the server. The application requires the Java Runtime Environment 1.4 or higher, which can be automatically downloaded from Sun Microsystems or Apple Computer and installed during the first use of Ligand.Info on desktop systems, which support Java (Ms Windows, Mac OS, Solaris, and Linux). The Ligand.Info Meta-Database can be used for virtual high-throughput screening of new potential drugs. Presented examples showed that using a known antiviral drug as query the system was able to find others antiviral drugs and inhibitors.

Virtual Technologies to Develop Visual-Spatial Ability in Engineering Students

ERIC Educational Resources Information Center

Roca-González, Cristina; Martin-Gutierrez, Jorge; García-Dominguez, Melchor; Carrodeguas, Mª del Carmen Mato

2017-01-01

The present study assessed a short training experiment to improve spatial abilities using two tools based on virtual technologies: one focused on manipulation of specific geometric virtual pieces, and the other consisting of virtual orienteering game. The two tools can help improve spatial abilities required for many engineering problem-solving…

Experimental validation and model development for thermal transmittances of porous window screens and horizontal louvred blind systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hart, Robert; Goudey, Howdy; Curcija, D. Charlie

Virtually every home in the US has some form of shades, blinds, drapes, or other window attachment, but few have been designed for energy savings. In order to provide a common basis of comparison for thermal performance it is important to have validated simulation tools. This study outlines a review and validation of the ISO 15099 centre-of-glass thermal transmittance correlations for naturally ventilated cavities through measurement and detailed simulations. The focus is on the impacts of room-side ventilated cavities, such as those found with solar screens and horizontal louvred blinds. The thermal transmittance of these systems is measured experimentally, simulatedmore » using computational fluid dynamics analysis, and simulated utilizing simplified correlations from ISO 15099. Finally, correlation coefficients are proposed for the ISO 15099 algorithm that reduces the mean error between measured and simulated heat flux for typical solar screens from 16% to 3.5% and from 13% to 1% for horizontal blinds.« less

Experimental validation and model development for thermal transmittances of porous window screens and horizontal louvred blind systems

DOE PAGES

Hart, Robert; Goudey, Howdy; Curcija, D. Charlie

2017-05-16

Virtually every home in the US has some form of shades, blinds, drapes, or other window attachment, but few have been designed for energy savings. In order to provide a common basis of comparison for thermal performance it is important to have validated simulation tools. This study outlines a review and validation of the ISO 15099 centre-of-glass thermal transmittance correlations for naturally ventilated cavities through measurement and detailed simulations. The focus is on the impacts of room-side ventilated cavities, such as those found with solar screens and horizontal louvred blinds. The thermal transmittance of these systems is measured experimentally, simulatedmore » using computational fluid dynamics analysis, and simulated utilizing simplified correlations from ISO 15099. Finally, correlation coefficients are proposed for the ISO 15099 algorithm that reduces the mean error between measured and simulated heat flux for typical solar screens from 16% to 3.5% and from 13% to 1% for horizontal blinds.« less

Immersive 3D Visualization of Astronomical Data

NASA Astrophysics Data System (ADS)

Schaaff, A.; Berthier, J.; Da Rocha, J.; Deparis, N.; Derriere, S.; Gaultier, P.; Houpin, R.; Normand, J.; Ocvirk, P.

2015-09-01

The immersive-3D visualization, or Virtual Reality in our study, was previously dedicated to specific uses (research, flight simulators, etc.) The investment in infrastructure and its cost was reserved to large laboratories or companies. Lately we saw the development of immersive-3D masks intended for wide distribution, for example the Oculus Rift and the Sony Morpheus projects. The usual reaction is to say that these tools are primarily intended for games since it is easy to imagine a player in a virtual environment and the added value to conventional 2D screens. Yet it is likely that there are many applications in the professional field if these tools are becoming common. Introducing this technology into existing applications or new developments makes sense only if interest is properly evaluated. The use in Astronomy is clear for education, it is easy to imagine mobile and light planetariums or to reproduce poorly accessible environments (e.g., large instruments). In contrast, in the field of professional astronomy the use is probably less obvious and it requires to conduct studies to determine the most appropriate ones and to assess the contributions compared to the other display modes.

The Use of Virtual Reality Tools in the Reading-Language Arts Classroom

ERIC Educational Resources Information Center

Pilgrim, J. Michael; Pilgrim, Jodi

2016-01-01

This article presents virtual reality as a tool for classroom literacy instruction. Building on the traditional use of images as a way to scaffold prior knowledge, we extend this idea to share ways virtual reality enables experiential learning through field trip-like experiences. The use of technology tools such Google Street view, Google…

A desirability-based multi objective approach for the virtual screening discovery of broad-spectrum anti-gastric cancer agents

PubMed Central

Sánchez-Rodríguez, Aminael; Tejera, Eduardo; Cruz-Monteagudo, Maykel; Borges, Fernanda; Cordeiro, M. Natália D. S.; Le-Thi-Thu, Huong; Pham-The, Hai

2018-01-01

Gastric cancer is the third leading cause of cancer-related mortality worldwide and despite advances in prevention, diagnosis and therapy, it is still regarded as a global health concern. The efficacy of the therapies for gastric cancer is limited by a poor response to currently available therapeutic regimens. One of the reasons that may explain these poor clinical outcomes is the highly heterogeneous nature of this disease. In this sense, it is essential to discover new molecular agents capable of targeting various gastric cancer subtypes simultaneously. Here, we present a multi-objective approach for the ligand-based virtual screening discovery of chemical compounds simultaneously active against the gastric cancer cell lines AGS, NCI-N87 and SNU-1. The proposed approach relays in a novel methodology based on the development of ensemble models for the bioactivity prediction against each individual gastric cancer cell line. The methodology includes the aggregation of one ensemble per cell line using a desirability-based algorithm into virtual screening protocols. Our research leads to the proposal of a multi-targeted virtual screening protocol able to achieve high enrichment of known chemicals with anti-gastric cancer activity. Specifically, our results indicate that, using the proposed protocol, it is possible to retrieve almost 20 more times multi-targeted compounds in the first 1% of the ranked list than what is expected from a uniform distribution of the active ones in the virtual screening database. More importantly, the proposed protocol attains an outstanding initial enrichment of known multi-targeted anti-gastric cancer agents. PMID:29420638

Application of Shape Similarity in Pose Selection and Virtual Screening in CSARdock2014 Exercise.

PubMed

Kumar, Ashutosh; Zhang, Kam Y J

2016-06-27

To evaluate the applicability of shape similarity in docking-based pose selection and virtual screening, we participated in the CSARdock2014 benchmark exercise for identifying the correct docking pose of inhibitors targeting factor XA, spleen tyrosine kinase, and tRNA methyltransferase. This exercise provides a valuable opportunity for researchers to test their docking programs, methods, and protocols in a blind testing environment. In the CSARdock2014 benchmark exercise, we have implemented an approach that uses ligand 3D shape similarity to facilitate docking-based pose selection and virtual screening. We showed here that ligand 3D shape similarity between bound poses could be used to identify the native-like pose from an ensemble of docking-generated poses. Our method correctly identified the native pose as the top-ranking pose for 73% of test cases in a blind testing environment. Moreover, the pose selection results also revealed an excellent correlation between ligand 3D shape similarity scores and RMSD to X-ray crystal structure ligand. In the virtual screening exercise, the average RMSD for our pose prediction was found to be 1.02 Å, and it was one of the top performances achieved in CSARdock2014 benchmark exercise. Furthermore, the inclusion of shape similarity improved virtual screening performance of docking-based scoring and ranking. The coefficient of determination (r(2)) between experimental activities and docking scores for 276 spleen tyrosine kinase inhibitors was found to be 0.365 but reached 0.614 when the ligand 3D shape similarity was included.

The Role of Affordances in Children's Learning Performance and Efficiency When Using Virtual Manipulative Mathematics Touch-Screen Apps

ERIC Educational Resources Information Center

Moyer-Packenham, Patricia S.; Bullock, Emma K.; Shumway, Jessica F.; Tucker, Stephen I.; Watts, Christina M.; Westenskow, Arla; Anderson-Pence, Katie L.; Maahs-Fladung, Cathy; Boyer-Thurgood, Jennifer; Gulkilik, Hilal; Jordan, Kerry

2016-01-01

This paper focuses on understanding the role that affordances played in children's learning performance and efficiency during clinical interviews of their interactions with mathematics apps on touch-screen devices. One hundred children, ages 3 to 8, each used six different virtual manipulative mathematics apps during 30-40-min interviews. The…

Virtual Screening and Pharmacophore Design for a Novel Theoretical Inhibitor of Macrophage Stimulating Factor as a Metastatic Agent

PubMed Central

Torktaz, Ibrahim; Mohamadhashem, Faezeh; Esmaeili, Abolghasem; Behjati, Mohaddeseh; Sharifzadeh, Sara

2013-01-01

Introduction: Metastasis is a crucial aspect of cancer. Macrophage stimulating protein (MSP) is a single chain protein and can be cleaved by serum proteases. MSP has several roles in metastasis. In this in silico study, MSP as a metastatic agent was considered as a drug target. Methods: Crystallographic structure of MSP was retrieved from protein data bank. To find a chemical inhibitor of MSP, a library of KEGG compounds was screened and 1000 shape complemented ligands were retrieved with FindSite algorithm. Molegro Virtual Docker (MVD) software was used for docking simulation of shape complemented ligands against MSP. Moldock score was used as scoring function for virtual screening and potential inhibitors with more negative binding energy were obtained. PLANS scoring function was used for revaluation of virtual screening data. Results: The top found chemical had binding affinity of -183.55 based on MolDock score and equal to -66.733 PLANTs score to MSP structure. Conclusion: Based on pharmacophore model of potential inhibitor, this study suggests that the chemical which was found in this research and its derivate can be used for subsequent laboratory studies. PMID:24163807

Combining in silico and in cerebro approaches for virtual screening and pose prediction in SAMPL4.

PubMed

Voet, Arnout R D; Kumar, Ashutosh; Berenger, Francois; Zhang, Kam Y J

2014-04-01

The SAMPL challenges provide an ideal opportunity for unbiased evaluation and comparison of different approaches used in computational drug design. During the fourth round of this SAMPL challenge, we participated in the virtual screening and binding pose prediction on inhibitors targeting the HIV-1 integrase enzyme. For virtual screening, we used well known and widely used in silico methods combined with personal in cerebro insights and experience. Regular docking only performed slightly better than random selection, but the performance was significantly improved upon incorporation of additional filters based on pharmacophore queries and electrostatic similarities. The best performance was achieved when logical selection was added. For the pose prediction, we utilized a similar consensus approach that amalgamated the results of the Glide-XP docking with structural knowledge and rescoring. The pose prediction results revealed that docking displayed reasonable performance in predicting the binding poses. However, prediction performance can be improved utilizing scientific experience and rescoring approaches. In both the virtual screening and pose prediction challenges, the top performance was achieved by our approaches. Here we describe the methods and strategies used in our approaches and discuss the rationale of their performances.

Combining in silico and in cerebro approaches for virtual screening and pose prediction in SAMPL4

NASA Astrophysics Data System (ADS)

Voet, Arnout R. D.; Kumar, Ashutosh; Berenger, Francois; Zhang, Kam Y. J.

2014-04-01

The SAMPL challenges provide an ideal opportunity for unbiased evaluation and comparison of different approaches used in computational drug design. During the fourth round of this SAMPL challenge, we participated in the virtual screening and binding pose prediction on inhibitors targeting the HIV-1 integrase enzyme. For virtual screening, we used well known and widely used in silico methods combined with personal in cerebro insights and experience. Regular docking only performed slightly better than random selection, but the performance was significantly improved upon incorporation of additional filters based on pharmacophore queries and electrostatic similarities. The best performance was achieved when logical selection was added. For the pose prediction, we utilized a similar consensus approach that amalgamated the results of the Glide-XP docking with structural knowledge and rescoring. The pose prediction results revealed that docking displayed reasonable performance in predicting the binding poses. However, prediction performance can be improved utilizing scientific experience and rescoring approaches. In both the virtual screening and pose prediction challenges, the top performance was achieved by our approaches. Here we describe the methods and strategies used in our approaches and discuss the rationale of their performances.

Hit Identification and Optimization in Virtual Screening: Practical Recommendations Based Upon a Critical Literature Analysis

PubMed Central

Zhu, Tian; Cao, Shuyi; Su, Pin-Chih; Patel, Ram; Shah, Darshan; Chokshi, Heta B.; Szukala, Richard; Johnson, Michael E.; Hevener, Kirk E.

2013-01-01

A critical analysis of virtual screening results published between 2007 and 2011 was performed. The activity of reported hit compounds from over 400 studies was compared to their hit identification criteria. Hit rates and ligand efficiencies were calculated to assist in these analyses and the results were compared with factors such as the size of the virtual library and the number of compounds tested. A series of promiscuity, drug-like, and ADMET filters were applied to the reported hits to assess the quality of compounds reported and a careful analysis of a subset of the studies which presented hit optimization was performed. This data allowed us to make several practical recommendations with respect to selection of compounds for experimental testing, defining hit identification criteria, and general virtual screening hit criteria to allow for realistic hit optimization. A key recommendation is the use of size-targeted ligand efficiency values as hit identification criteria. PMID:23688234

Modeling and simulation of five-axis virtual machine based on NX

NASA Astrophysics Data System (ADS)

Li, Xiaoda; Zhan, Xianghui

2018-04-01

Virtual technology in the machinery manufacturing industry has shown the role of growing. In this paper, the Siemens NX software is used to model the virtual CNC machine tool, and the parameters of the virtual machine are defined according to the actual parameters of the machine tool so that the virtual simulation can be carried out without loss of the accuracy of the simulation. How to use the machine builder of the CAM module to define the kinematic chain and machine components of the machine is described. The simulation of virtual machine can provide alarm information of tool collision and over cutting during the process to users, and can evaluate and forecast the rationality of the technological process.

Discovery of new GSK-3β inhibitors through structure-based virtual screening.

PubMed

Dou, Xiaodong; Jiang, Lan; Wang, Yanxing; Jin, Hongwei; Liu, Zhenming; Zhang, Liangren

2018-01-15

Glycogen synthase kinase-3β (GSK-3β) is an attractive therapeutic target for human diseases, such as diabetes, cancer, neurodegenerative diseases, and inflammation. Thus, structure-based virtual screening was performed to identify novel scaffolds of GSK-3β inhibitors, and we observed that conserved water molecules of GSK-3β were suitable for virtual screening. We found 14 hits and D1 (IC 50 of 0.71 μM) were identified. Furthermore, the neuroprotection activity of D1-D3 was validated on a cellular level. 2D similarity searches were used to find derivatives of high inhibitory compounds and an enriched structure-activity relationship suggested that these skeletons were worthy of study as potent GSK-3β inhibitors. Copyright © 2017. Published by Elsevier Ltd.

Modeling and Deorphanization of Orphan GPCRs.

PubMed

Diaz, Constantino; Angelloz-Nicoud, Patricia; Pihan, Emilie

2018-01-01

Despite tremendous efforts, approximately 120 GPCRs remain orphan. Their physiological functions and their potential roles in diseases are poorly understood. Orphan GPCRs are extremely important because they may provide novel therapeutic targets for unmet medical needs. As a complement to experimental approaches, molecular modeling and virtual screening are efficient techniques to discover synthetic surrogate ligands which can help to elucidate the role of oGPCRs. Constitutively activated mutants and recently published active structures of GPCRs provide stimulating opportunities for building active molecular models for oGPCRs and identifying activators using virtual screening of compound libraries. We describe the molecular modeling and virtual screening process we have applied in the discovery of surrogate ligands, and provide examples for CCKA, a simulated oGPCR, and for two oGPCRs, GPR52 and GPR34.

3D Virtual Reality Check: Learner Engagement and Constructivist Theory

ERIC Educational Resources Information Center

Bair, Richard A.

2013-01-01

The inclusion of three-dimensional (3D) virtual tools has created a need to communicate the engagement of 3D tools and specify learning gains that educators and the institutions, which are funding 3D tools, can expect. A review of literature demonstrates that specific models and theories for 3D Virtual Reality (VR) learning do not exist "per…

The importance of employing computational resources for the automation of drug discovery.

PubMed

Rosales-Hernández, Martha Cecilia; Correa-Basurto, José

2015-03-01

The application of computational tools to drug discovery helps researchers to design and evaluate new drugs swiftly with a reduce economic resources. To discover new potential drugs, computational chemistry incorporates automatization for obtaining biological data such as adsorption, distribution, metabolism, excretion and toxicity (ADMET), as well as drug mechanisms of action. This editorial looks at examples of these computational tools, including docking, molecular dynamics simulation, virtual screening, quantum chemistry, quantitative structural activity relationship, principal component analysis and drug screening workflow systems. The authors then provide their perspectives on the importance of these techniques for drug discovery. Computational tools help researchers to design and discover new drugs for the treatment of several human diseases without side effects, thus allowing for the evaluation of millions of compounds with a reduced cost in both time and economic resources. The problem is that operating each program is difficult; one is required to use several programs and understand each of the properties being tested. In the future, it is possible that a single computer and software program will be capable of evaluating the complete properties (mechanisms of action and ADMET properties) of ligands. It is also possible that after submitting one target, this computer-software will be capable of suggesting potential compounds along with ways to synthesize them, and presenting biological models for testing.

Structure-Based Virtual Screening for Drug Discovery: Principles, Applications and Recent Advances

PubMed Central

Lionta, Evanthia; Spyrou, George; Vassilatis, Demetrios K.; Cournia, Zoe

2014-01-01

Structure-based drug discovery (SBDD) is becoming an essential tool in assisting fast and cost-efficient lead discovery and optimization. The application of rational, structure-based drug design is proven to be more efficient than the traditional way of drug discovery since it aims to understand the molecular basis of a disease and utilizes the knowledge of the three-dimensional structure of the biological target in the process. In this review, we focus on the principles and applications of Virtual Screening (VS) within the context of SBDD and examine different procedures ranging from the initial stages of the process that include receptor and library pre-processing, to docking, scoring and post-processing of topscoring hits. Recent improvements in structure-based virtual screening (SBVS) efficiency through ensemble docking, induced fit and consensus docking are also discussed. The review highlights advances in the field within the framework of several success studies that have led to nM inhibition directly from VS and provides recent trends in library design as well as discusses limitations of the method. Applications of SBVS in the design of substrates for engineered proteins that enable the discovery of new metabolic and signal transduction pathways and the design of inhibitors of multifunctional proteins are also reviewed. Finally, we contribute two promising VS protocols recently developed by us that aim to increase inhibitor selectivity. In the first protocol, we describe the discovery of micromolar inhibitors through SBVS designed to inhibit the mutant H1047R PI3Kα kinase. Second, we discuss a strategy for the identification of selective binders for the RXRα nuclear receptor. In this protocol, a set of target structures is constructed for ensemble docking based on binding site shape characterization and clustering, aiming to enhance the hit rate of selective inhibitors for the desired protein target through the SBVS process. PMID:25262799

Quantitative structure-activity relationship analysis and virtual screening studies for identifying HDAC2 inhibitors from known HDAC bioactive chemical libraries.

PubMed

Pham-The, H; Casañola-Martin, G; Diéguez-Santana, K; Nguyen-Hai, N; Ngoc, N T; Vu-Duc, L; Le-Thi-Thu, H

2017-03-01

Histone deacetylases (HDAC) are emerging as promising targets in cancer, neuronal diseases and immune disorders. Computational modelling approaches have been widely applied for the virtual screening and rational design of novel HDAC inhibitors. In this study, different machine learning (ML) techniques were applied for the development of models that accurately discriminate HDAC2 inhibitors form non-inhibitors. The obtained models showed encouraging results, with the global accuracy in the external set ranging from 0.83 to 0.90. Various aspects related to the comparison of modelling techniques, applicability domain and descriptor interpretations were discussed. Finally, consensus predictions of these models were used for screening HDAC2 inhibitors from four chemical libraries whose bioactivities against HDAC1, HDAC3, HDAC6 and HDAC8 have been known. According to the results of virtual screening assays, structures of some hits with pair-isoform-selective activity (between HDAC2 and other HDACs) were revealed. This study illustrates the power of ML-based QSAR approaches for the screening and discovery of potent, isoform-selective HDACIs.

Molecular Docking and Drug Discovery in β-Adrenergic Receptors.

PubMed

Vilar, Santiago; Sobarzo-Sanchez, Eduardo; Santana, Lourdes; Uriarte, Eugenio

2017-01-01

Evolution in computer engineering, availability of increasing amounts of data and the development of new and fast docking algorithms and software have led to improved molecular simulations with crucial applications in virtual high-throughput screening and drug discovery. Moreover, analysis of protein-ligand recognition through molecular docking has become a valuable tool in drug design. In this review, we focus on the applicability of molecular docking on a particular class of G protein-coupled receptors: the β-adrenergic receptors, which are relevant targets in clinic for the treatment of asthma and cardiovascular diseases. We describe the binding site in β-adrenergic receptors to understand key factors in ligand recognition along with the proteins activation process. Moreover, we focus on the discovery of new lead compounds that bind the receptors, on the evaluation of virtual screening using the active/ inactive binding site states, and on the structural optimization of known families of binders to improve β-adrenergic affinity. We also discussed strengths and challenges related to the applicability of molecular docking in β-adrenergic receptors. Molecular docking is a valuable technique in computational chemistry to deeply analyze ligand recognition and has led to important breakthroughs in drug discovery and design in the field of β-adrenergic receptors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

PSOVina: The hybrid particle swarm optimization algorithm for protein-ligand docking.

PubMed

Ng, Marcus C K; Fong, Simon; Siu, Shirley W I

2015-06-01

Protein-ligand docking is an essential step in modern drug discovery process. The challenge here is to accurately predict and efficiently optimize the position and orientation of ligands in the binding pocket of a target protein. In this paper, we present a new method called PSOVina which combined the particle swarm optimization (PSO) algorithm with the efficient Broyden-Fletcher-Goldfarb-Shannon (BFGS) local search method adopted in AutoDock Vina to tackle the conformational search problem in docking. Using a diverse data set of 201 protein-ligand complexes from the PDBbind database and a full set of ligands and decoys for four representative targets from the directory of useful decoys (DUD) virtual screening data set, we assessed the docking performance of PSOVina in comparison to the original Vina program. Our results showed that PSOVina achieves a remarkable execution time reduction of 51-60% without compromising the prediction accuracies in the docking and virtual screening experiments. This improvement in time efficiency makes PSOVina a better choice of a docking tool in large-scale protein-ligand docking applications. Our work lays the foundation for the future development of swarm-based algorithms in molecular docking programs. PSOVina is freely available to non-commercial users at http://cbbio.cis.umac.mo .

Novel colchicine-site binders with a cyclohexanedione scaffold identified through a ligand-based virtual screening approach.

PubMed

Canela, María-Dolores; Pérez-Pérez, María-Jesús; Noppen, Sam; Sáez-Calvo, Gonzalo; Díaz, J Fernando; Camarasa, María-José; Liekens, Sandra; Priego, Eva-María

2014-05-22

Vascular disrupting agents (VDAs) constitute an innovative anticancer therapy that targets the tumor endothelium, leading to tumor necrosis. Our approach for the identification of new VDAs has relied on a ligand 3-D shape similarity virtual screening (VS) approach using the ROCS program as the VS tool and as query colchicine and TN-16, which both bind the α,β-tubulin dimer. One of the hits identified, using TN-16 as query, has been explored by the synthesis of its structural analogues, leading to 2-(1-((2-methoxyphenyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione (compound 16c) with an IC50 = 0.09 ± 0.01 μM in HMEC-1 and BAEC, being 100-fold more potent than the initial hit. Compound 16c caused cell cycle arrest in the G2/M phase and interacted with the colchicine-binding site in tubulin, as confirmed by a competition assay with N,N'-ethylenebis(iodoacetamide) and by fluorescence spectroscopy. Moreover, 16c destroyed an established endothelial tubular network at 1 μM and inhibited the migration and invasion of human breast carcinoma cells at 0.4 μM. In conclusion, our approach has led to a new chemotype of promising antiproliferative compounds with antimitotic and potential VDA properties.

Computational Toxicology at the US EPA | Science Inventory ...

EPA Pesticide Factsheets

Computational toxicology is the application of mathematical and computer models to help assess chemical hazards and risks to human health and the environment. Supported by advances in informatics, high-throughput screening (HTS) technologies, and systems biology, EPA is developing robust and flexible computational tools that can be applied to the thousands of chemicals in commerce, and contaminant mixtures found in America’s air, water, and hazardous-waste sites. The ORD Computational Toxicology Research Program (CTRP) is composed of three main elements. The largest component is the National Center for Computational Toxicology (NCCT), which was established in 2005 to coordinate research on chemical screening and prioritization, informatics, and systems modeling. The second element consists of related activities in the National Health and Environmental Effects Research Laboratory (NHEERL) and the National Exposure Research Laboratory (NERL). The third and final component consists of academic centers working on various aspects of computational toxicology and funded by the EPA Science to Achieve Results (STAR) program. Key intramural projects of the CTRP include digitizing legacy toxicity testing information toxicity reference database (ToxRefDB), predicting toxicity (ToxCast™) and exposure (ExpoCast™), and creating virtual liver (v-Liver™) and virtual embryo (v-Embryo™) systems models. The models and underlying data are being made publicly available t

Virtual screening of selective multitarget kinase inhibitors by combinatorial support vector machines.

PubMed

Ma, X H; Wang, R; Tan, C Y; Jiang, Y Y; Lu, T; Rao, H B; Li, X Y; Go, M L; Low, B C; Chen, Y Z

2010-10-04

Multitarget agents have been increasingly explored for enhancing efficacy and reducing countertarget activities and toxicities. Efficient virtual screening (VS) tools for searching selective multitarget agents are desired. Combinatorial support vector machines (C-SVM) were tested as VS tools for searching dual-inhibitors of 11 combinations of 9 anticancer kinase targets (EGFR, VEGFR, PDGFR, Src, FGFR, Lck, CDK1, CDK2, GSK3). C-SVM trained on 233-1,316 non-dual-inhibitors correctly identified 26.8%-57.3% (majority >36%) of the 56-230 intra-kinase-group dual-inhibitors (equivalent to the 50-70% yields of two independent individual target VS tools), and 12.2% of the 41 inter-kinase-group dual-inhibitors. C-SVM were fairly selective in misidentifying as dual-inhibitors 3.7%-48.1% (majority <20%) of the 233-1,316 non-dual-inhibitors of the same kinase pairs and 0.98%-4.77% of the 3,971-5,180 inhibitors of other kinases. C-SVM produced low false-hit rates in misidentifying as dual-inhibitors 1,746-4,817 (0.013%-0.036%) of the 13.56 M PubChem compounds, 12-175 (0.007%-0.104%) of the 168 K MDDR compounds, and 0-84 (0.0%-2.9%) of the 19,495-38,483 MDDR compounds similar to the known dual-inhibitors. C-SVM was compared to other VS methods Surflex-Dock, DOCK Blaster, kNN and PNN against the same sets of kinase inhibitors and the full set or subset of the 1.02 M Zinc clean-leads data set. C-SVM produced comparable dual-inhibitor yields, slightly better false-hit rates for kinase inhibitors, and significantly lower false-hit rates for the Zinc clean-leads data set. Combinatorial SVM showed promising potential for searching selective multitarget agents against intra-kinase-group kinases without explicit knowledge of multitarget agents.

Chemoinformatics Profiling of the Chromone Nucleus as a MAO-B/A2AAR Dual Binding Scaffold

PubMed Central

Cruz-Monteagudo, Maykel; Borges, Fernanda; Cordeiro, M. Natália D. S.; Helguera, Aliuska Morales; Tejera, Eduardo; Paz-y-Miño, Cesar; Sánchez-Rodríguez, Aminael; Perera-Sardiña, Yunier; Perez-Castillo, Yunierkis

2017-01-01

Background: In the context of the current drug discovery efforts to find disease modifying therapies for Parkinson´s disease (PD) the current single target strategy has proved inefficient. Consequently, the search for multi-potent agents is attracting more and more attention due to the multiple pathogenetic factors implicated in PD. Multiple evidences points to the dual inhibition of the monoamine oxidase B (MAO-B), as well as adenosine A2A receptor (A2AAR) blockade, as a promising approach to prevent the neurodegeneration involved in PD. Currently, only two chemical scaffolds has been proposed as potential dual MAO-B inhibitors/A2AAR antagonists (caffeine derivatives and benzothiazinones). Methods: In this study, we conduct a series of chemoinformatics analysis in order to evaluate and advance the potential of the chromone nucleus as a MAO-B/A2AAR dual binding scaffold. Results: The information provided by SAR data mining analysis based on network similarity graphs and molecular docking studies support the suitability of the chromone nucleus as a potential MAO-B/A2AAR dual binding scaffold. Additionally, a virtual screening tool based on a group fusion similarity search approach was developed for the prioritization of potential MAO-B/A2AAR dual binder candidates. Among several data fusion schemes evaluated, the MEAN-SIM and MIN-RANK GFSS approaches demonstrated to be efficient virtual screening tools. Then, a combinatorial library potentially enriched with MAO-B/A2AAR dual binding chromone derivatives was assembled and sorted by using the MIN-RANK and then the MEAN-SIM GFSS VS approaches. Conclusion: The information and tools provided in this work represent valuable decision making elements in the search of novel chromone derivatives with a favorable dual binding profile as MAO-B inhibitors and A2AAR antagonists with the potential to act as a disease-modifying therapeutic for Parkinson´s disease. PMID:28093976

A method for evaluating the performance of computer-aided detection of pulmonary nodules in lung cancer CT screening: detection limit for nodule size and density

PubMed Central

Kobayashi, Hajime; Ohkubo, Masaki; Narita, Akihiro; Marasinghe, Janaka C; Murao, Kohei; Matsumoto, Toru; Sone, Shusuke

2017-01-01

Objective: We propose the application of virtual nodules to evaluate the performance of computer-aided detection (CAD) of lung nodules in cancer screening using low-dose CT. Methods: The virtual nodules were generated based on the spatial resolution measured for a CT system used in an institution providing cancer screening and were fused into clinical lung images obtained at that institution, allowing site specificity. First, we validated virtual nodules as an alternative to artificial nodules inserted into a phantom. In addition, we compared the results of CAD analysis between the real nodules (n = 6) and the corresponding virtual nodules. Subsequently, virtual nodules of various sizes and contrasts between nodule density and background density (ΔCT) were inserted into clinical images (n = 10) and submitted for CAD analysis. Results: In the validation study, 46 of 48 virtual nodules had the same CAD results as artificial nodules (kappa coefficient = 0.913). Real nodules and the corresponding virtual nodules showed the same CAD results. The detection limits of the tested CAD system were determined in terms of size and density of peripheral lung nodules; we demonstrated that a nodule with a 5-mm diameter was detected when the nodule had a ΔCT > 220 HU. Conclusion: Virtual nodules are effective in evaluating CAD performance using site-specific scan/reconstruction conditions. Advances in knowledge: Virtual nodules can be an effective means of evaluating site-specific CAD performance. The methodology for guiding the detection limit for nodule size/density might be a useful evaluation strategy. PMID:27897029

Grid heterogeneity in in-silico experiments: an exploration of drug screening using DOCK on cloud environments.

PubMed

Yim, Wen-Wai; Chien, Shu; Kusumoto, Yasuyuki; Date, Susumu; Haga, Jason

2010-01-01

Large-scale in-silico screening is a necessary part of drug discovery and Grid computing is one answer to this demand. A disadvantage of using Grid computing is the heterogeneous computational environments characteristic of a Grid. In our study, we have found that for the molecular docking simulation program DOCK, different clusters within a Grid organization can yield inconsistent results. Because DOCK in-silico virtual screening (VS) is currently used to help select chemical compounds to test with in-vitro experiments, such differences have little effect on the validity of using virtual screening before subsequent steps in the drug discovery process. However, it is difficult to predict whether the accumulation of these discrepancies over sequentially repeated VS experiments will significantly alter the results if VS is used as the primary means for identifying potential drugs. Moreover, such discrepancies may be unacceptable for other applications requiring more stringent thresholds. This highlights the need for establishing a more complete solution to provide the best scientific accuracy when executing an application across Grids. One possible solution to platform heterogeneity in DOCK performance explored in our study involved the use of virtual machines as a layer of abstraction. This study investigated the feasibility and practicality of using virtual machine and recent cloud computing technologies in a biological research application. We examined the differences and variations of DOCK VS variables, across a Grid environment composed of different clusters, with and without virtualization. The uniform computer environment provided by virtual machines eliminated inconsistent DOCK VS results caused by heterogeneous clusters, however, the execution time for the DOCK VS increased. In our particular experiments, overhead costs were found to be an average of 41% and 2% in execution time for two different clusters, while the actual magnitudes of the execution time costs were minimal. Despite the increase in overhead, virtual clusters are an ideal solution for Grid heterogeneity. With greater development of virtual cluster technology in Grid environments, the problem of platform heterogeneity may be eliminated through virtualization, allowing greater usage of VS, and will benefit all Grid applications in general.

History Educators and the Challenge of Immersive Pasts: A Critical Review of Virtual Reality "Tools" and History Pedagogy

ERIC Educational Resources Information Center

Allison, John

2008-01-01

This paper will undertake a critical review of the impact of virtual reality tools on the teaching of history. Virtual reality is useful in several different ways. History educators, elementary and secondary school teachers and professors, can all profit from the digital environment. Challenges arise quickly however. Virtual reality technologies…

Virtual Laboratory "vs." Traditional Laboratory: Which Is More Effective for Teaching Electrochemistry?

ERIC Educational Resources Information Center

Hawkins, Ian; Phelps, Amy J.

2013-01-01

The use of virtual laboratories has become an increasing issue regarding science laboratories due to the increasing cost of hands-on laboratories, and the increase in distance education. Recent studies have looked at the use of virtual tools for laboratory to be used as supplements to the regular hands-on laboratories but many virtual tools have…

Virtual screening and optimization of Type II inhibitors of JAK2 from a natural product library.

PubMed

Ma, Dik-Lung; Chan, Daniel Shiu-Hin; Wei, Guo; Zhong, Hai-Jing; Yang, Hui; Leung, Lai To; Gullen, Elizabeth A; Chiu, Pauline; Cheng, Yung-Chi; Leung, Chung-Hang

2014-11-21

Amentoflavone has been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library. In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo. Molecular modeling and kinetic experiments suggested that the analogues may function as Type II inhibitors of JAK2.

Use of Virtual Reality Tools for Vestibular Disorders Rehabilitation: A Comprehensive Analysis.

PubMed

Bergeron, Mathieu; Lortie, Catherine L; Guitton, Matthieu J

2015-01-01

Classical peripheral vestibular disorders rehabilitation is a long and costly process. While virtual reality settings have been repeatedly suggested to represent possible tools to help the rehabilitation process, no systematic study had been conducted so far. We systematically reviewed the current literature to analyze the published protocols documenting the use of virtual reality settings for peripheral vestibular disorders rehabilitation. There is an important diversity of settings and protocols involving virtual reality settings for the treatment of this pathology. Evaluation of the symptoms is often not standardized. However, our results unveil a clear effect of virtual reality settings-based rehabilitation of the patients' symptoms, assessed by objectives tools such as the DHI (mean decrease of 27 points), changing symptoms handicap perception from moderate to mild impact on life. Furthermore, we detected a relationship between the duration of the exposure to virtual reality environments and the magnitude of the therapeutic effects, suggesting that virtual reality treatments should last at least 150 minutes of cumulated exposure to ensure positive outcomes. Virtual reality offers a pleasant and safe environment for the patient. Future studies should standardize evaluation tools, document putative side effects further, compare virtual reality to conventional physical therapy, and evaluate economical costs/benefits of such strategies.

Use of Virtual Reality Tools for Vestibular Disorders Rehabilitation: A Comprehensive Analysis

PubMed Central

Bergeron, Mathieu; Lortie, Catherine L.; Guitton, Matthieu J.

2015-01-01

Classical peripheral vestibular disorders rehabilitation is a long and costly process. While virtual reality settings have been repeatedly suggested to represent possible tools to help the rehabilitation process, no systematic study had been conducted so far. We systematically reviewed the current literature to analyze the published protocols documenting the use of virtual reality settings for peripheral vestibular disorders rehabilitation. There is an important diversity of settings and protocols involving virtual reality settings for the treatment of this pathology. Evaluation of the symptoms is often not standardized. However, our results unveil a clear effect of virtual reality settings-based rehabilitation of the patients' symptoms, assessed by objectives tools such as the DHI (mean decrease of 27 points), changing symptoms handicap perception from moderate to mild impact on life. Furthermore, we detected a relationship between the duration of the exposure to virtual reality environments and the magnitude of the therapeutic effects, suggesting that virtual reality treatments should last at least 150 minutes of cumulated exposure to ensure positive outcomes. Virtual reality offers a pleasant and safe environment for the patient. Future studies should standardize evaluation tools, document putative side effects further, compare virtual reality to conventional physical therapy, and evaluate economical costs/benefits of such strategies. PMID:26556560

A virtual therapeutic environment with user projective agents.

PubMed

Ookita, S Y; Tokuda, H

2001-02-01

Today, we see the Internet as more than just an information infrastructure, but a socializing place and a safe outlet of inner feelings. Many personalities develop aside from real world life due to its anonymous environment. Virtual world interactions are bringing about new psychological illnesses ranging from netaddiction to technostress, as well as online personality disorders and conflicts in multiple identities that exist in the virtual world. Presently, there are no standard therapy models for the virtual environment. There are very few therapeutic environments, or tools especially made for virtual therapeutic environments. The goal of our research is to provide the therapy model and middleware tools for psychologists to use in virtual therapeutic environments. We propose the Cyber Therapy Model, and Projective Agents, a tool used in the therapeutic environment. To evaluate the effectiveness of the tool, we created a prototype system, called the Virtual Group Counseling System, which is a therapeutic environment that allows the user to participate in group counseling through the eyes of their Projective Agent. Projective Agents inherit the user's personality traits. During the virtual group counseling, the user's Projective Agent interacts and collaborates to recover and increase their psychological growth. The prototype system provides a simulation environment where psychologists can adjust the parameters and customize their own simulation environment. The model and tool is a first attempt toward simulating online personalities that may exist only online, and provide data for observation.

The effectiveness of virtual reality interventions in improving balance in adults with impaired balance compared with standard or no treatment: a systematic review and meta-analysis.

PubMed

Booth, Vicky; Masud, Tahir; Connell, Louise; Bath-Hextall, Fiona

2014-05-01

To evaluate whether virtual reality interventions, including interactive gaming systems, are effective at improving balance in adults with impaired balance. Systematic review and meta-analysis of randomized control trials. Studies were identified from electronic databases (CENTRAL, MEDLINE, EMBASE, AMED, CINAHL, PyschINFO, PyschBITE, OTseeker, Ei Compendex, and Inspec) searched to November 2011, and repeated in November 2012. Two reviewers selected studies meeting inclusion criteria and quality of included studies assessed using a Joanna Briggs Institute appraisal tool. Data was pooled and a meta-analysis completed. The systematic review was reported following guidance of the PRISMA statement. A total of 251 articles were screened. Eight randomized control trials were included. These studies presented the results of 239 participants, with various aetiologies, and used a variety of virtual reality systems. The number of falls was documented in only one included study. Meta-analysis was completed on data from the Berg Balance Scale, walking speed, 30 second sit-to-stand test, and Timed Up and Go Test, and favoured standard therapy when compared with standard plus virtual reality interventions. There was a notable inconsistency in the outcome measures, experimental, and control interventions used within the included studies. The pooled results of the studies showed no significant difference. Therefore this review cannot support nor refute the use of virtual reality interventions, rather than conventional physiotherapy, to improve balance in adults with impaired balance.

Performance Studies on Distributed Virtual Screening

PubMed Central

Krüger, Jens; de la Garza, Luis; Kohlbacher, Oliver; Nagel, Wolfgang E.

2014-01-01

Virtual high-throughput screening (vHTS) is an invaluable method in modern drug discovery. It permits screening large datasets or databases of chemical structures for those structures binding possibly to a drug target. Virtual screening is typically performed by docking code, which often runs sequentially. Processing of huge vHTS datasets can be parallelized by chunking the data because individual docking runs are independent of each other. The goal of this work is to find an optimal splitting maximizing the speedup while considering overhead and available cores on Distributed Computing Infrastructures (DCIs). We have conducted thorough performance studies accounting not only for the runtime of the docking itself, but also for structure preparation. Performance studies were conducted via the workflow-enabled science gateway MoSGrid (Molecular Simulation Grid). As input we used benchmark datasets for protein kinases. Our performance studies show that docking workflows can be made to scale almost linearly up to 500 concurrent processes distributed even over large DCIs, thus accelerating vHTS campaigns significantly. PMID:25032219

Novel Design Strategy for Checkpoint Kinase 2 Inhibitors Using Pharmacophore Modeling, Combinatorial Fusion, and Virtual Screening

PubMed Central

Wang, Yen-Ling

2014-01-01

Checkpoint kinase 2 (Chk2) has a great effect on DNA-damage and plays an important role in response to DNA double-strand breaks and related lesions. In this study, we will concentrate on Chk2 and the purpose is to find the potential inhibitors by the pharmacophore hypotheses (PhModels), combinatorial fusion, and virtual screening techniques. Applying combinatorial fusion into PhModels and virtual screening techniques is a novel design strategy for drug design. We used combinatorial fusion to analyze the prediction results and then obtained the best correlation coefficient of the testing set (r test) with the value 0.816 by combining the BesttrainBesttest and FasttrainFasttest prediction results. The potential inhibitors were selected from NCI database by screening according to BesttrainBesttest + FasttrainFasttest prediction results and molecular docking with CDOCKER docking program. Finally, the selected compounds have high interaction energy between a ligand and a receptor. Through these approaches, 23 potential inhibitors for Chk2 are retrieved for further study. PMID:24864236

Application of QSAR and shape pharmacophore modeling approaches for targeted chemical library design.

PubMed

Ebalunode, Jerry O; Zheng, Weifan; Tropsha, Alexander

2011-01-01

Optimization of chemical library composition affords more efficient identification of hits from biological screening experiments. The optimization could be achieved through rational selection of reagents used in combinatorial library synthesis. However, with a rapid advent of parallel synthesis methods and availability of millions of compounds synthesized by many vendors, it may be more efficient to design targeted libraries by means of virtual screening of commercial compound collections. This chapter reviews the application of advanced cheminformatics approaches such as quantitative structure-activity relationships (QSAR) and pharmacophore modeling (both ligand and structure based) for virtual screening. Both approaches rely on empirical SAR data to build models; thus, the emphasis is placed on achieving models of the highest rigor and external predictive power. We present several examples of successful applications of both approaches for virtual screening to illustrate their utility. We suggest that the expert use of both QSAR and pharmacophore models, either independently or in combination, enables users to achieve targeted libraries enriched with experimentally confirmed hit compounds.

Evaluation of a novel virtual screening strategy using receptor decoy binding sites.

PubMed

Patel, Hershna; Kukol, Andreas

2016-08-23

Virtual screening is used in biomedical research to predict the binding affinity of a large set of small organic molecules to protein receptor targets. This report shows the development and evaluation of a novel yet straightforward attempt to improve this ranking in receptor-based molecular docking using a receptor-decoy strategy. This strategy includes defining a decoy binding site on the receptor and adjusting the ranking of the true binding-site virtual screen based on the decoy-site screen. The results show that by docking against a receptor-decoy site with Autodock Vina, improved Receiver Operator Characteristic Enrichment (ROCE) was achieved for 5 out of fifteen receptor targets investigated, when up to 15 % of a decoy site rank list was considered. No improved enrichment was seen for 7 targets, while for 3 targets the ROCE was reduced. The extent to which this strategy can effectively improve ligand prediction is dependent on the target receptor investigated.

Novel Inhibitors of Mycobacterium tuberculosis dTDP-6-deoxy-L-lyxo-4-hexulose Reductase (RmlD) Identified by Virtual Screening

PubMed Central

Wang, Yi; Hess, Tamara Noelle; Jones, Victoria; Zhou, Joe Zhongxiang; McNeil, Michael R.; McCammon, J. Andrew

2011-01-01

The complex and highly impermeable cell wall of Mycobacterium tuberculosis (Mtb) is largely responsible for the ability of the mycobacterium to resist the action of chemical therapeutics. An L-rhamnosyl residue, which occupies an important anchoring position in the Mtb cell wall, is an attractive target for novel anti-tuberculosis drugs. In this work, we report a virtual screening (VS) study targeting Mtb dTDP-deoxy-L-lyxo-4-hexulose reductase (RmlD), the last enzyme in the L-rhamnosyl synthesis pathway. Through two rounds of VS, we have identified four RmlD inhibitors with half inhibitory concentrations of 0.9-25 μM, and whole-cell minimum inhibitory concentrations of 20-200 μg/ml. Compared with our previous high throughput screening targeting another enzyme involved in L-rhamnosyl synthesis, virtual screening produced higher hit rates, supporting the use of computational methods in future anti-tuberculosis drug discovery efforts. PMID:22014548

A cross docking pipeline for improving pose prediction and virtual screening performance

NASA Astrophysics Data System (ADS)

Kumar, Ashutosh; Zhang, Kam Y. J.

2018-01-01

Pose prediction and virtual screening performance of a molecular docking method depend on the choice of protein structures used for docking. Multiple structures for a target protein are often used to take into account the receptor flexibility and problems associated with a single receptor structure. However, the use of multiple receptor structures is computationally expensive when docking a large library of small molecules. Here, we propose a new cross-docking pipeline suitable to dock a large library of molecules while taking advantage of multiple target protein structures. Our method involves the selection of a suitable receptor for each ligand in a screening library utilizing ligand 3D shape similarity with crystallographic ligands. We have prospectively evaluated our method in D3R Grand Challenge 2 and demonstrated that our cross-docking pipeline can achieve similar or better performance than using either single or multiple-receptor structures. Moreover, our method displayed not only decent pose prediction performance but also better virtual screening performance over several other methods.

Search for β2 Adrenergic Receptor Ligands by Virtual Screening via Grid Computing and Investigation of Binding Modes by Docking and Molecular Dynamics Simulations

PubMed Central

Bai, Qifeng; Shao, Yonghua; Pan, Dabo; Zhang, Yang; Liu, Huanxiang; Yao, Xiaojun

2014-01-01

We designed a program called MolGridCal that can be used to screen small molecule database in grid computing on basis of JPPF grid environment. Based on MolGridCal program, we proposed an integrated strategy for virtual screening and binding mode investigation by combining molecular docking, molecular dynamics (MD) simulations and free energy calculations. To test the effectiveness of MolGridCal, we screened potential ligands for β2 adrenergic receptor (β2AR) from a database containing 50,000 small molecules. MolGridCal can not only send tasks to the grid server automatically, but also can distribute tasks using the screensaver function. As for the results of virtual screening, the known agonist BI-167107 of β2AR is ranked among the top 2% of the screened candidates, indicating MolGridCal program can give reasonable results. To further study the binding mode and refine the results of MolGridCal, more accurate docking and scoring methods are used to estimate the binding affinity for the top three molecules (agonist BI-167107, neutral antagonist alprenolol and inverse agonist ICI 118,551). The results indicate agonist BI-167107 has the best binding affinity. MD simulation and free energy calculation are employed to investigate the dynamic interaction mechanism between the ligands and β2AR. The results show that the agonist BI-167107 also has the lowest binding free energy. This study can provide a new way to perform virtual screening effectively through integrating molecular docking based on grid computing, MD simulations and free energy calculations. The source codes of MolGridCal are freely available at http://molgridcal.codeplex.com. PMID:25229694

High-immersion three-dimensional display of the numerical computer model

NASA Astrophysics Data System (ADS)

Xing, Shujun; Yu, Xunbo; Zhao, Tianqi; Cai, Yuanfa; Chen, Duo; Chen, Zhidong; Sang, Xinzhu

2013-08-01

High-immersion three-dimensional (3D) displays making them valuable tools for many applications, such as designing and constructing desired building houses, industrial architecture design, aeronautics, scientific research, entertainment, media advertisement, military areas and so on. However, most technologies provide 3D display in the front of screens which are in parallel with the walls, and the sense of immersion is decreased. To get the right multi-view stereo ground image, cameras' photosensitive surface should be parallax to the public focus plane and the cameras' optical axes should be offset to the center of public focus plane both atvertical direction and horizontal direction. It is very common to use virtual cameras, which is an ideal pinhole camera to display 3D model in computer system. We can use virtual cameras to simulate the shooting method of multi-view ground based stereo image. Here, two virtual shooting methods for ground based high-immersion 3D display are presented. The position of virtual camera is determined by the people's eye position in the real world. When the observer stand in the circumcircle of 3D ground display, offset perspective projection virtual cameras is used. If the observer stands out the circumcircle of 3D ground display, offset perspective projection virtual cameras and the orthogonal projection virtual cameras are adopted. In this paper, we mainly discussed the parameter setting of virtual cameras. The Near Clip Plane parameter setting is the main point in the first method, while the rotation angle of virtual cameras is the main point in the second method. In order to validate the results, we use the D3D and OpenGL to render scenes of different viewpoints and generate a stereoscopic image. A realistic visualization system for 3D models is constructed and demonstrated for viewing horizontally, which provides high-immersion 3D visualization. The displayed 3D scenes are compared with the real objects in the real world.

Perception of Graphical Virtual Environments by Blind Users via Sensory Substitution

PubMed Central

Maidenbaum, Shachar; Buchs, Galit; Abboud, Sami; Lavi-Rotbain, Ori; Amedi, Amir

2016-01-01

Graphical virtual environments are currently far from accessible to blind users as their content is mostly visual. This is especially unfortunate as these environments hold great potential for this population for purposes such as safe orientation, education, and entertainment. Previous tools have increased accessibility but there is still a long way to go. Visual-to-audio Sensory-Substitution-Devices (SSDs) can increase accessibility generically by sonifying on-screen content regardless of the specific environment and offer increased accessibility without the use of expensive dedicated peripherals like electrode/vibrator arrays. Using SSDs virtually utilizes similar skills as when using them in the real world, enabling both training on the device and training on environments virtually before real-world visits. This could enable more complex, standardized and autonomous SSD training and new insights into multisensory interaction and the visually-deprived brain. However, whether congenitally blind users, who have never experienced virtual environments, will be able to use this information for successful perception and interaction within them is currently unclear.We tested this using the EyeMusic SSD, which conveys whole-scene visual information, to perform virtual tasks otherwise impossible without vision. Congenitally blind users had to navigate virtual environments and find doors, differentiate between them based on their features (Experiment1:task1) and surroundings (Experiment1:task2) and walk through them; these tasks were accomplished with a 95% and 97% success rate, respectively. We further explored the reactions of congenitally blind users during their first interaction with a more complex virtual environment than in the previous tasks–walking down a virtual street, recognizing different features of houses and trees, navigating to cross-walks, etc. Users reacted enthusiastically and reported feeling immersed within the environment. They highlighted the potential usefulness of such environments for understanding what visual scenes are supposed to look like and their potential for complex training and suggested many future environments they wished to experience. PMID:26882473

Perception of Graphical Virtual Environments by Blind Users via Sensory Substitution.

PubMed

Maidenbaum, Shachar; Buchs, Galit; Abboud, Sami; Lavi-Rotbain, Ori; Amedi, Amir

2016-01-01

Graphical virtual environments are currently far from accessible to blind users as their content is mostly visual. This is especially unfortunate as these environments hold great potential for this population for purposes such as safe orientation, education, and entertainment. Previous tools have increased accessibility but there is still a long way to go. Visual-to-audio Sensory-Substitution-Devices (SSDs) can increase accessibility generically by sonifying on-screen content regardless of the specific environment and offer increased accessibility without the use of expensive dedicated peripherals like electrode/vibrator arrays. Using SSDs virtually utilizes similar skills as when using them in the real world, enabling both training on the device and training on environments virtually before real-world visits. This could enable more complex, standardized and autonomous SSD training and new insights into multisensory interaction and the visually-deprived brain. However, whether congenitally blind users, who have never experienced virtual environments, will be able to use this information for successful perception and interaction within them is currently unclear.We tested this using the EyeMusic SSD, which conveys whole-scene visual information, to perform virtual tasks otherwise impossible without vision. Congenitally blind users had to navigate virtual environments and find doors, differentiate between them based on their features (Experiment1:task1) and surroundings (Experiment1:task2) and walk through them; these tasks were accomplished with a 95% and 97% success rate, respectively. We further explored the reactions of congenitally blind users during their first interaction with a more complex virtual environment than in the previous tasks-walking down a virtual street, recognizing different features of houses and trees, navigating to cross-walks, etc. Users reacted enthusiastically and reported feeling immersed within the environment. They highlighted the potential usefulness of such environments for understanding what visual scenes are supposed to look like and their potential for complex training and suggested many future environments they wished to experience.

GeauxDock: Accelerating Structure-Based Virtual Screening with Heterogeneous Computing

PubMed Central

Fang, Ye; Ding, Yun; Feinstein, Wei P.; Koppelman, David M.; Moreno, Juana; Jarrell, Mark; Ramanujam, J.; Brylinski, Michal

2016-01-01

Computational modeling of drug binding to proteins is an integral component of direct drug design. Particularly, structure-based virtual screening is often used to perform large-scale modeling of putative associations between small organic molecules and their pharmacologically relevant protein targets. Because of a large number of drug candidates to be evaluated, an accurate and fast docking engine is a critical element of virtual screening. Consequently, highly optimized docking codes are of paramount importance for the effectiveness of virtual screening methods. In this communication, we describe the implementation, tuning and performance characteristics of GeauxDock, a recently developed molecular docking program. GeauxDock is built upon the Monte Carlo algorithm and features a novel scoring function combining physics-based energy terms with statistical and knowledge-based potentials. Developed specifically for heterogeneous computing platforms, the current version of GeauxDock can be deployed on modern, multi-core Central Processing Units (CPUs) as well as massively parallel accelerators, Intel Xeon Phi and NVIDIA Graphics Processing Unit (GPU). First, we carried out a thorough performance tuning of the high-level framework and the docking kernel to produce a fast serial code, which was then ported to shared-memory multi-core CPUs yielding a near-ideal scaling. Further, using Xeon Phi gives 1.9× performance improvement over a dual 10-core Xeon CPU, whereas the best GPU accelerator, GeForce GTX 980, achieves a speedup as high as 3.5×. On that account, GeauxDock can take advantage of modern heterogeneous architectures to considerably accelerate structure-based virtual screening applications. GeauxDock is open-sourced and publicly available at www.brylinski.org/geauxdock and https://figshare.com/articles/geauxdock_tar_gz/3205249. PMID:27420300

Virtual screening filters for the design of type II p38 MAP kinase inhibitors: a fragment based library generation approach.

PubMed

Badrinarayan, Preethi; Sastry, G Narahari

2012-04-01

In this work, we introduce the development and application of a three-step scoring and filtering procedure for the design of type II p38 MAP kinase leads using allosteric fragments extracted from virtual screening hits. The design of the virtual screening filters is based on a thorough evaluation of docking methods, DFG-loop conformation, binding interactions and chemotype specificity of the 138 p38 MAP kinase inhibitors from Protein Data Bank bound to DFG-in and DFG-out conformations using Glide, GOLD and CDOCKER. A 40 ns molecular dynamics simulation with the apo, type I with DFG-in and type II with DFG-out forms was carried out to delineate the effects of structural variations on inhibitor binding. The designed docking-score and sub-structure filters were first tested on a dataset of 249 potent p38 MAP kinase inhibitors from seven diverse series and 18,842 kinase inhibitors from PDB, to gauge their capacity to discriminate between kinase and non-kinase inhibitors and likewise to selectively filter-in target-specific inhibitors. The designed filters were then applied in the virtual screening of a database of ten million (10⁷) compounds resulting in the identification of 100 hits. Based on their binding modes, 98 allosteric fragments were extracted from the hits and a fragment library was generated. New type II p38 MAP kinase leads were designed by tailoring the existing type I ATP site binders with allosteric fragments using a common urea linker. Target specific virtual screening filters can thus be easily developed for other kinases based on this strategy to retrieve target selective compounds. Copyright © 2012 Elsevier Inc. All rights reserved.

In silico approaches to identify novel myeloid cell leukemia-1 (Mcl-1) inhibitors for treatment of cancer.

PubMed

Ren, Ji-Xia; Li, Cheng-Ping; Zhou, Xiu-Ling; Cao, Xue-Song; Xie, Yong

2017-08-22

Myeloid cell leukemia-1 (Mcl-1) has been a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to the resistance to current chemotherapeutics. Here, we identified new Mcl-1 inhibitors using a multi-step virtual screening approach. First, based on two different ligand-receptor complexes, 20 pharmacophore models were established by simultaneously using 'Receptor-Ligand Pharmacophore Generation' method and manual build feature method, and then carefully validated by a test database. Then, pharmacophore-based virtual screening (PB-VS) could be performed by using the 20 pharmacophore models. In addition, docking study was used to predict the possible binding poses of compounds, and the docking parameters were optimized before performing docking-based virtual screening (DB-VS). Moreover, a 3D QSAR model was established by applying the 55 aligned Mcl-1 inhibitors. The 55 inhibitors sharing the same scaffold were docked into the Mcl-1 active site before alignment, then the inhibitors with possible binding conformations were aligned. For the training set, the 3D QSAR model gave a correlation coefficient r 2 of 0.996; for the test set, the correlation coefficient r 2 was 0.812. Therefore, the developed 3D QSAR model was a good model, which could be applied for carrying out 3D QSAR-based virtual screening (QSARD-VS). After the above three virtual screening methods orderly filtering, 23 potential inhibitors with novel scaffolds were identified. Furthermore, we have discussed in detail the mapping results of two potent compounds onto pharmacophore models, 3D QSAR model, and the interactions between the compounds and active site residues.

GeauxDock: Accelerating Structure-Based Virtual Screening with Heterogeneous Computing.

PubMed

Fang, Ye; Ding, Yun; Feinstein, Wei P; Koppelman, David M; Moreno, Juana; Jarrell, Mark; Ramanujam, J; Brylinski, Michal

2016-01-01

Computational modeling of drug binding to proteins is an integral component of direct drug design. Particularly, structure-based virtual screening is often used to perform large-scale modeling of putative associations between small organic molecules and their pharmacologically relevant protein targets. Because of a large number of drug candidates to be evaluated, an accurate and fast docking engine is a critical element of virtual screening. Consequently, highly optimized docking codes are of paramount importance for the effectiveness of virtual screening methods. In this communication, we describe the implementation, tuning and performance characteristics of GeauxDock, a recently developed molecular docking program. GeauxDock is built upon the Monte Carlo algorithm and features a novel scoring function combining physics-based energy terms with statistical and knowledge-based potentials. Developed specifically for heterogeneous computing platforms, the current version of GeauxDock can be deployed on modern, multi-core Central Processing Units (CPUs) as well as massively parallel accelerators, Intel Xeon Phi and NVIDIA Graphics Processing Unit (GPU). First, we carried out a thorough performance tuning of the high-level framework and the docking kernel to produce a fast serial code, which was then ported to shared-memory multi-core CPUs yielding a near-ideal scaling. Further, using Xeon Phi gives 1.9× performance improvement over a dual 10-core Xeon CPU, whereas the best GPU accelerator, GeForce GTX 980, achieves a speedup as high as 3.5×. On that account, GeauxDock can take advantage of modern heterogeneous architectures to considerably accelerate structure-based virtual screening applications. GeauxDock is open-sourced and publicly available at www.brylinski.org/geauxdock and https://figshare.com/articles/geauxdock_tar_gz/3205249.

Colorectal Cancer Screening

MedlinePlus

... blood test Sigmoidoscopy Colonoscopy Virtual colonoscopy DNA stool test Studies have shown that screening for colorectal cancer using ... decrease the risk of dying from cancer. Scientists study screening tests to find those with the fewest risks and ...

A kinase-focused compound collection: compilation and screening strategy.

PubMed

Sun, Dongyu; Chuaqui, Claudio; Deng, Zhan; Bowes, Scott; Chin, Donovan; Singh, Juswinder; Cullen, Patrick; Hankins, Gretchen; Lee, Wen-Cherng; Donnelly, Jason; Friedman, Jessica; Josiah, Serene

2006-06-01

Lead identification by high-throughput screening of large compound libraries has been supplemented with virtual screening and focused compound libraries. To complement existing approaches for lead identification at Biogen Idec, a kinase-focused compound collection was designed, developed and validated. Two strategies were adopted to populate the compound collection: a ligand shape-based virtual screening and a receptor-based approach (structural interaction fingerprint). Compounds selected with the two approaches were cherry-picked from an existing high-throughput screening compound library, ordered from suppliers and supplemented with specific medicinal compounds from internal programs. Promising hits and leads have been generated from the kinase-focused compound collection against multiple kinase targets. The principle of the collection design and screening strategy was validated and the use of the kinase-focused compound collection for lead identification has been added to existing strategies.

Efficient method for high-throughput virtual screening based on flexible docking: discovery of novel acetylcholinesterase inhibitors.

PubMed

Mizutani, Miho Yamada; Itai, Akiko

2004-09-23

A method of easily finding ligands, with a variety of core structures, for a given target macromolecule would greatly contribute to the rapid identification of novel lead compounds for drug development. We have developed an efficient method for discovering ligand candidates from a number of flexible compounds included in databases, when the three-dimensional (3D) structure of the drug target is available. The method, named ADAM&EVE, makes use of our automated docking method ADAM, which has already been reported. Like ADAM, ADAM&EVE takes account of the flexibility of each molecule in databases, by exploring the conformational space fully and continuously. Database screening has been made much faster than with ADAM through the tuning of parameters, so that computational screening of several hundred thousand compounds is possible in a practical time. Promising ligand candidates can be selected according to various criteria based on the docking results and characteristics of compounds. Furthermore, we have developed a new tool, EVE-MAKE, for automatically preparing the additional compound data necessary for flexible docking calculation, prior to 3D database screening. Among several successful cases of lead discovery by ADAM&EVE, the finding of novel acetylcholinesterase (AChE) inhibitors is presented here. We performed a virtual screening of about 160 000 commercially available compounds against the X-ray crystallographic structure of AChE. Among 114 compounds that could be purchased and assayed, 35 molecules with various core structures showed inhibitory activities with IC(50) values less than 100 microM. Thirteen compounds had IC(50) values between 0.5 and 10 microM, and almost all their core structures are very different from those of known inhibitors. The results demonstrate the effectiveness and validity of the ADAM&EVE approach and provide a starting point for development of novel drugs to treat Alzheimer's disease.

Virtual High-Throughput Screening for Matrix Metalloproteinase Inhibitors.

PubMed

Choi, Jun Yong; Fuerst, Rita

2017-01-01

Structure-based virtual screening (SBVS) is a common method for the fast identification of hit structures at the beginning of a medicinal chemistry program in drug discovery. The SBVS, described in this manuscript, is focused on finding small molecule hits that can be further utilized as a starting point for the development of inhibitors of matrix metalloproteinase 13 (MMP-13) via structure-based molecular design. We intended to identify a set of structurally diverse hits, which occupy all subsites (S1'-S3', S2, and S3) centering the zinc containing binding site of MMP-13, by the virtual screening of a chemical library comprising more than ten million commercially available compounds. In total, 23 compounds were found as potential MMP-13 inhibitors using Glide docking followed by the analysis of the structural interaction fingerprints (SIFt) of the docked structures.

Free Energy-Based Virtual Screening and Optimization of RNase H Inhibitors of HIV-1 Reverse Transcriptase.

PubMed

Zhang, Baofeng; D'Erasmo, Michael P; Murelli, Ryan P; Gallicchio, Emilio

2016-09-30

We report the results of a binding free energy-based virtual screening campaign of a library of 77 α-hydroxytropolone derivatives against the challenging RNase H active site of the reverse transcriptase (RT) enzyme of human immunodeficiency virus-1. Multiple protonation states, rotamer states, and binding modalities of each compound were individually evaluated. The work involved more than 300 individual absolute alchemical binding free energy parallel molecular dynamics calculations and over 1 million CPU hours on national computing clusters and a local campus computational grid. The thermodynamic and structural measures obtained in this work rationalize a series of characteristics of this system useful for guiding future synthetic and biochemical efforts. The free energy model identified key ligand-dependent entropic and conformational reorganization processes difficult to capture using standard docking and scoring approaches. Binding free energy-based optimization of the lead compounds emerging from the virtual screen has yielded four compounds with very favorable binding properties, which will be the subject of further experimental investigations. This work is one of the few reported applications of advanced-binding free energy models to large-scale virtual screening and optimization projects. It further demonstrates that, with suitable algorithms and automation, advanced-binding free energy models can have a useful role in early-stage drug-discovery programs.

Congestion game scheduling for virtual drug screening optimization

NASA Astrophysics Data System (ADS)

Nikitina, Natalia; Ivashko, Evgeny; Tchernykh, Andrei

2018-02-01

In virtual drug screening, the chemical diversity of hits is an important factor, along with their predicted activity. Moreover, interim results are of interest for directing the further research, and their diversity is also desirable. In this paper, we consider a problem of obtaining a diverse set of virtual screening hits in a short time. To this end, we propose a mathematical model of task scheduling for virtual drug screening in high-performance computational systems as a congestion game between computational nodes to find the equilibrium solutions for best balancing the number of interim hits with their chemical diversity. The model considers the heterogeneous environment with workload uncertainty, processing time uncertainty, and limited knowledge about the input dataset structure. We perform computational experiments and evaluate the performance of the developed approach considering organic molecules database GDB-9. The used set of molecules is rich enough to demonstrate the feasibility and practicability of proposed solutions. We compare the algorithm with two known heuristics used in practice and observe that game-based scheduling outperforms them by the hit discovery rate and chemical diversity at earlier steps. Based on these results, we use a social utility metric for assessing the efficiency of our equilibrium solutions and show that they reach greatest values.

Risks of Colorectal Cancer Screening

MedlinePlus

... blood test Sigmoidoscopy Colonoscopy Virtual colonoscopy DNA stool test Studies have shown that screening for colorectal cancer using ... decrease the risk of dying from cancer. Scientists study screening tests to find those with the fewest risks and ...

gWEGA: GPU-accelerated WEGA for molecular superposition and shape comparison.

PubMed

Yan, Xin; Li, Jiabo; Gu, Qiong; Xu, Jun

2014-06-05

Virtual screening of a large chemical library for drug lead identification requires searching/superimposing a large number of three-dimensional (3D) chemical structures. This article reports a graphic processing unit (GPU)-accelerated weighted Gaussian algorithm (gWEGA) that expedites shape or shape-feature similarity score-based virtual screening. With 86 GPU nodes (each node has one GPU card), gWEGA can screen 110 million conformations derived from an entire ZINC drug-like database with diverse antidiabetic agents as query structures within 2 s (i.e., screening more than 55 million conformations per second). The rapid screening speed was accomplished through the massive parallelization on multiple GPU nodes and rapid prescreening of 3D structures (based on their shape descriptors and pharmacophore feature compositions). Copyright © 2014 Wiley Periodicals, Inc.

Library fingerprints: a novel approach to the screening of virtual libraries.

PubMed

Klon, Anthony E; Diller, David J

2007-01-01

We propose a novel method to prioritize libraries for combinatorial synthesis and high-throughput screening that assesses the viability of a particular library on the basis of the aggregate physical-chemical properties of the compounds using a naïve Bayesian classifier. This approach prioritizes collections of related compounds according to the aggregate values of their physical-chemical parameters in contrast to single-compound screening. The method is also shown to be useful in screening existing noncombinatorial libraries when the compounds in these libraries have been previously clustered according to their molecular graphs. We show that the method used here is comparable or superior to the single-compound virtual screening of combinatorial libraries and noncombinatorial libraries and is superior to the pairwise Tanimoto similarity searching of a collection of combinatorial libraries.

Virtual Surgery for the Nasal Airway: A Preliminary Report on Decision Support and Technology Acceptance.

PubMed

Vanhille, Derek L; Garcia, Guilherme J M; Asan, Onur; Borojeni, Azadeh A T; Frank-Ito, Dennis O; Kimbell, Julia S; Pawar, Sachin S; Rhee, John S

2018-01-01

Nasal airway obstruction (NAO) is a common problem that affects patient quality of life. Surgical success for NAO correction is variable. Virtual surgery planning via computational fluid dynamics (CFD) has the potential to improve the success rates of NAO surgery. To elicit surgeon feedback of a virtual surgery planning tool for NAO and to determine if this tool affects surgeon decision making. For this cross-sectional study, 60-minute face-to-face interviews with board-certified otolaryngologists were conducted at a single academic otolaryngology department from September 16, 2016, through October 7, 2016. Virtual surgery methods were introduced, and surgeons were able to interact with the virtual surgery planning tool interface. Surgeons were provided with a patient case of NAO, and open feedback of the platform was obtained, with emphasis on surgical decision making. Likert scale responses and qualitative feedback were collected for the virtual surgery planning tool and its influence on surgeon decision making. Our 9 study participants were all male, board-certified otolaryngologists with a mean (range) 15 (4-28) number of years in practice and a mean (range) number of nasal surgeries per month at 2.2 (0.0-6.0). When examined on a scale of 1 (not at all) to 5 (completely), surgeon mean (SD) score was 3.4 (0.5) for how realistic the virtual models were compared with actual surgery. On the same scale, when asked how much the virtual surgery planning tool changed surgeon decision making, mean (SD) score was 2.6 (1.6). On a scale of 1 (strongly disagree) to 7 (strongly agree), surgeon scores for perceived usefulness of the technology and attitude toward using it were 5.1 (1.1) and 5.7 (0.9), respectively. Our study shows positive surgeon experience with a virtual surgery planning tool for NAO based on CFD simulations. Surgeons felt that future applications and areas of study of the virtual surgery planning tool include its potential role for patient counseling, selecting appropriate surgical candidates, and identifying which anatomical structures should be targeted for surgical correction. NA.

Early phase drug discovery: cheminformatics and computational techniques in identifying lead series.

PubMed

Duffy, Bryan C; Zhu, Lei; Decornez, Hélène; Kitchen, Douglas B

2012-09-15

Early drug discovery processes rely on hit finding procedures followed by extensive experimental confirmation in order to select high priority hit series which then undergo further scrutiny in hit-to-lead studies. The experimental cost and the risk associated with poor selection of lead series can be greatly reduced by the use of many different computational and cheminformatic techniques to sort and prioritize compounds. We describe the steps in typical hit identification and hit-to-lead programs and then describe how cheminformatic analysis assists this process. In particular, scaffold analysis, clustering and property calculations assist in the design of high-throughput screening libraries, the early analysis of hits and then organizing compounds into series for their progression from hits to leads. Additionally, these computational tools can be used in virtual screening to design hit-finding libraries and as procedures to help with early SAR exploration. Copyright © 2012 Elsevier Ltd. All rights reserved.

An Overview of Evaluative Instrumentation for Virtual High Schools

ERIC Educational Resources Information Center

Black, Erik W.; Ferdig, Richard E.; DiPietro, Meredith

2008-01-01

With an increasing prevalence of virtual high school programs in the United States, a better understanding of evaluative tools available for distance educators and administrators is needed. These evaluative tools would provide opportunities for assessment and a determination of success within virtual schools. This article seeks to provide an…

Accelerating Virtual High-Throughput Ligand Docking: current technology and case study on a petascale supercomputer.

PubMed

Ellingson, Sally R; Dakshanamurthy, Sivanesan; Brown, Milton; Smith, Jeremy C; Baudry, Jerome

2014-04-25

In this paper we give the current state of high-throughput virtual screening. We describe a case study of using a task-parallel MPI (Message Passing Interface) version of Autodock4 [1], [2] to run a virtual high-throughput screen of one-million compounds on the Jaguar Cray XK6 Supercomputer at Oak Ridge National Laboratory. We include a description of scripts developed to increase the efficiency of the predocking file preparation and postdocking analysis. A detailed tutorial, scripts, and source code for this MPI version of Autodock4 are available online at http://www.bio.utk.edu/baudrylab/autodockmpi.htm.

Structure Based Virtual Screening Studies to Identify Novel Potential Compounds for GPR142 and Their Relative Dynamic Analysis for Study of Type 2 Diabetes

NASA Astrophysics Data System (ADS)

Kaushik, Aman C.; Kumar, Sanjay; Wei, Dong Q.; Sahi, Shakti

2018-02-01

GPR142 (G protein receptor 142) is a novel orphan GPCR (G protein coupled receptor) belonging to ‘Class A’ of GPCR family and expressed in beta cells of pancreas. In this study, we reported the structure based virtual screening to identify the hit compounds which can be developed as leads for potential agonists. The results were validated through induced fit docking, pharmacophore modeling and system biology approaches. Since, there is no solved crystal structure of GPR142, we attempted to predict the 3D structure followed by validation and then identification of active site using threading and ab initio methods. Also, structure based virtual screening was performed against a total of 1171519 compounds from different libraries and only top 20 best hit compounds were screened and analyzed. Moreover, the biochemical pathway of GPR142 complex with screened compound2 was also designed and compared with experimental data. Interestingly, compound2 showed an increase in insulin production via Gq mediated signaling pathway suggesting the possible role of novel GPR142 agonists in therapy against type 2 diabetes.

Surflex-Dock: Docking benchmarks and real-world application

NASA Astrophysics Data System (ADS)

Spitzer, Russell; Jain, Ajay N.

2012-06-01

Benchmarks for molecular docking have historically focused on re-docking the cognate ligand of a well-determined protein-ligand complex to measure geometric pose prediction accuracy, and measurement of virtual screening performance has been focused on increasingly large and diverse sets of target protein structures, cognate ligands, and various types of decoy sets. Here, pose prediction is reported on the Astex Diverse set of 85 protein ligand complexes, and virtual screening performance is reported on the DUD set of 40 protein targets. In both cases, prepared structures of targets and ligands were provided by symposium organizers. The re-prepared data sets yielded results not significantly different than previous reports of Surflex-Dock on the two benchmarks. Minor changes to protein coordinates resulting from complex pre-optimization had large effects on observed performance, highlighting the limitations of cognate ligand re-docking for pose prediction assessment. Docking protocols developed for cross-docking, which address protein flexibility and produce discrete families of predicted poses, produced substantially better performance for pose prediction. Performance on virtual screening performance was shown to benefit by employing and combining multiple screening methods: docking, 2D molecular similarity, and 3D molecular similarity. In addition, use of multiple protein conformations significantly improved screening enrichment.

Human-scale interaction for virtual model displays: a clear case for real tools

NASA Astrophysics Data System (ADS)

Williams, George C.; McDowall, Ian E.; Bolas, Mark T.

1998-04-01

We describe a hand-held user interface for interacting with virtual environments displayed on a Virtual Model Display. The tool, constructed entirely of transparent materials, is see-through. We render a graphical counterpart of the tool on the display and map it one-to-one with the real tool. This feature, combined with a capability for touch- sensitive, discrete input, results in a useful spatial input device that is visually versatile. We discuss the tool's design and interaction techniques it supports. Briefly, we look at the human factors issues and engineering challenges presented by this tool and, in general, by the class of hand-held user interfaces that are see-through.

Discovery of a fluorene class of compounds as inhibitors of botulinum neurotoxin serotype E by virtual screening.

PubMed

Kumar, Gyanendra; Agarwal, Rakhi; Swaminathan, Subramanyam

2012-02-28

Botulinum neurotoxins are one of the most poisonous biological substances known to humans and present a potential bioterrorism threat. There are no therapeutic interventions developed so far. Here, we report the first small molecule non-peptide inhibitor for botulinum neurotoxin serotype E discovered by structure-based virtual screening and propose a mechanism for its inhibitory activity. This journal is © The Royal Society of Chemistry 2012

Ligand-based virtual screening and inductive learning for identification of SIRT1 inhibitors in natural products.

PubMed

Sun, Yunan; Zhou, Hui; Zhu, Hongmei; Leung, Siu-wai

2016-01-25

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase, and its dysregulation can lead to ageing, diabetes, and cancer. From 346 experimentally confirmed SIRT1 inhibitors, an inhibitor structure pattern was generated by inductive logic programming (ILP) with DMax Chemistry Assistant software. The pattern contained amide, amine, and hetero-aromatic five-membered rings, each of which had a hetero-atom and an unsubstituted atom at a distance of 2. According to this pattern, a ligand-based virtual screening of 1 444 880 active compounds from Chinese herbs identified 12 compounds as inhibitors of SIRT1. Three compounds (ZINC08790006, ZINC08792229, and ZINC08792355) had high affinity (-7.3, -7.8, and -8.6 kcal/mol, respectively) for SIRT1 as estimated by molecular docking software AutoDock Vina. This study demonstrated a use of ILP and background knowledge in machine learning to facilitate virtual screening.

Ligand-based virtual screening and inductive learning for identification of SIRT1 inhibitors in natural products

NASA Astrophysics Data System (ADS)

Sun, Yunan; Zhou, Hui; Zhu, Hongmei; Leung, Siu-Wai

2016-01-01

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase, and its dysregulation can lead to ageing, diabetes, and cancer. From 346 experimentally confirmed SIRT1 inhibitors, an inhibitor structure pattern was generated by inductive logic programming (ILP) with DMax Chemistry Assistant software. The pattern contained amide, amine, and hetero-aromatic five-membered rings, each of which had a hetero-atom and an unsubstituted atom at a distance of 2. According to this pattern, a ligand-based virtual screening of 1 444 880 active compounds from Chinese herbs identified 12 compounds as inhibitors of SIRT1. Three compounds (ZINC08790006, ZINC08792229, and ZINC08792355) had high affinity (-7.3, -7.8, and -8.6 kcal/mol, respectively) for SIRT1 as estimated by molecular docking software AutoDock Vina. This study demonstrated a use of ILP and background knowledge in machine learning to facilitate virtual screening.

Identification of DNA primase inhibitors via a combined fragment-based and virtual screening

NASA Astrophysics Data System (ADS)

Ilic, Stefan; Akabayov, Sabine R.; Arthanari, Haribabu; Wagner, Gerhard; Richardson, Charles C.; Akabayov, Barak

2016-11-01

The structural differences between bacterial and human primases render the former an excellent target for drug design. Here we describe a technique for selecting small molecule inhibitors of the activity of T7 DNA primase, an ideal model for bacterial primases due to their common structural and functional features. Using NMR screening, fragment molecules that bind T7 primase were identified and then exploited in virtual filtration to select larger molecules from the ZINC database. The molecules were docked to the primase active site using the available primase crystal structure and ranked based on their predicted binding energies to identify the best candidates for functional and structural investigations. Biochemical assays revealed that some of the molecules inhibit T7 primase-dependent DNA replication. The binding mechanism was delineated via NMR spectroscopy. Our approach, which combines fragment based and virtual screening, is rapid and cost effective and can be applied to other targets.

Discovery of potent inhibitors of soluble epoxide hydrolase by combinatorial library design and structure-based virtual screening.

PubMed

Xing, Li; McDonald, Joseph J; Kolodziej, Steve A; Kurumbail, Ravi G; Williams, Jennifer M; Warren, Chad J; O'Neal, Janet M; Skepner, Jill E; Roberds, Steven L

2011-03-10

Structure-based virtual screening was applied to design combinatorial libraries to discover novel and potent soluble epoxide hydrolase (sEH) inhibitors. X-ray crystal structures revealed unique interactions for a benzoxazole template in addition to the conserved hydrogen bonds with the catalytic machinery of sEH. By exploitation of the favorable binding elements, two iterations of library design based on amide coupling were employed, guided principally by the docking results of the enumerated virtual products. Biological screening of the libraries demonstrated as high as 90% hit rate, of which over two dozen compounds were single digit nanomolar sEH inhibitors by IC(50) determination. In total the library design and synthesis produced more than 300 submicromolar sEH inhibitors. In cellular systems consistent activities were demonstrated with biochemical measurements. The SAR understanding of the benzoxazole template provides valuable insights into discovery of novel sEH inhibitors as therapeutic agents.

Development of purely structure-based pharmacophores for the topoisomerase I-DNA-ligand binding pocket

NASA Astrophysics Data System (ADS)

Drwal, Malgorzata N.; Agama, Keli; Pommier, Yves; Griffith, Renate

2013-12-01

Purely structure-based pharmacophores (SBPs) are an alternative method to ligand-based approaches and have the advantage of describing the entire interaction capability of a binding pocket. Here, we present the development of SBPs for topoisomerase I, an anticancer target with an unusual ligand binding pocket consisting of protein and DNA atoms. Different approaches to cluster and select pharmacophore features are investigated, including hierarchical clustering and energy calculations. In addition, the performance of SBPs is evaluated retrospectively and compared to the performance of ligand- and complex-based pharmacophores. SBPs emerge as a valid method in virtual screening and a complementary approach to ligand-focussed methods. The study further reveals that the choice of pharmacophore feature clustering and selection methods has a large impact on the virtual screening hit lists. A prospective application of the SBPs in virtual screening reveals that they can be used successfully to identify novel topoisomerase inhibitors.

Three-dimensional compound comparison methods and their application in drug discovery.

PubMed

Shin, Woong-Hee; Zhu, Xiaolei; Bures, Mark Gregory; Kihara, Daisuke

2015-07-16

Virtual screening has been widely used in the drug discovery process. Ligand-based virtual screening (LBVS) methods compare a library of compounds with a known active ligand. Two notable advantages of LBVS methods are that they do not require structural information of a target receptor and that they are faster than structure-based methods. LBVS methods can be classified based on the complexity of ligand structure information utilized: one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D). Unlike 1D and 2D methods, 3D methods can have enhanced performance since they treat the conformational flexibility of compounds. In this paper, a number of 3D methods will be reviewed. In addition, four representative 3D methods were benchmarked to understand their performance in virtual screening. Specifically, we tested overall performance in key aspects including the ability to find dissimilar active compounds, and computational speed.

New Solutions for Enabling Discovery of User-Centric Virtual Data Products in NASA's Common Metadata Repository

NASA Astrophysics Data System (ADS)

Pilone, D.; Gilman, J.; Baynes, K.; Shum, D.

2015-12-01

This talk introduces a new NASA Earth Observing System Data and Information System (EOSDIS) capability to automatically generate and maintain derived, Virtual Product information allowing DAACs and Data Providers to create tailored and more discoverable variations of their products. After this talk the audience will be aware of the new EOSDIS Virtual Product capability, applications of it, and how to take advantage of it. Much of the data made available in the EOSDIS are organized for generation and archival rather than for discovery and use. The EOSDIS Common Metadata Repository (CMR) is launching a new capability providing automated generation and maintenance of user-oriented Virtual Product information. DAACs can easily surface variations on established data products tailored to specific uses cases and users, leveraging DAAC exposed services such as custom ordering or access services like OPeNDAP for on-demand product generation and distribution. Virtual Data Products enjoy support for spatial and temporal information, keyword discovery, association with imagery, and are fully discoverable by tools such as NASA Earthdata Search, Worldview, and Reverb. Virtual Product generation has applicability across many use cases: - Describing derived products such as Surface Kinetic Temperature information (AST_08) from source products (ASTER L1A) - Providing streamlined access to data products (e.g. AIRS) containing many (>800) data variables covering an enormous variety of physical measurements - Attaching additional EOSDIS offerings such as Visual Metadata, external services, and documentation metadata - Publishing alternate formats for a product (e.g. netCDF for HDF products) with the actual conversion happening on request - Publishing granules to be modified by on-the-fly services, like GES-DISC's Data Quality Screening Service - Publishing "bundled" products where granules from one product correspond to granules from one or more other related products

An augmented reality tool for learning spatial anatomy on mobile devices.

PubMed

Jain, Nishant; Youngblood, Patricia; Hasel, Matthew; Srivastava, Sakti

2017-09-01

Augmented Realty (AR) offers a novel method of blending virtual and real anatomy for intuitive spatial learning. Our first aim in the study was to create a prototype AR tool for mobile devices. Our second aim was to complete a technical evaluation of our prototype AR tool focused on measuring the system's ability to accurately render digital content in the real world. We imported Computed Tomography (CT) data derived virtual surface models into a 3D Unity engine environment and implemented an AR algorithm to display these on mobile devices. We investigated the accuracy of the virtual renderings by comparing a physical cube with an identical virtual cube for dimensional accuracy. Our comparative study confirms that our AR tool renders 3D virtual objects with a high level of accuracy as evidenced by the degree of similarity between measurements of the dimensions of a virtual object (a cube) and the corresponding physical object. We developed an inexpensive and user-friendly prototype AR tool for mobile devices that creates highly accurate renderings. This prototype demonstrates an intuitive, portable, and integrated interface for spatial interaction with virtual anatomical specimens. Integrating this AR tool with a library of CT derived surface models provides a platform for spatial learning in the anatomy curriculum. The segmentation methodology implemented to optimize human CT data for mobile viewing can be extended to include anatomical variations and pathologies. The ability of this inexpensive educational platform to deliver a library of interactive, 3D models to students worldwide demonstrates its utility as a supplemental teaching tool that could greatly benefit anatomical instruction. Clin. Anat. 30:736-741, 2017. © 2017Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

3D-Lab: a collaborative web-based platform for molecular modeling.

PubMed

Grebner, Christoph; Norrby, Magnus; Enström, Jonatan; Nilsson, Ingemar; Hogner, Anders; Henriksson, Jonas; Westin, Johan; Faramarzi, Farzad; Werner, Philip; Boström, Jonas

2016-09-01

The use of 3D information has shown impact in numerous applications in drug design. However, it is often under-utilized and traditionally limited to specialists. We want to change that, and present an approach making 3D information and molecular modeling accessible and easy-to-use 'for the people'. A user-friendly and collaborative web-based platform (3D-Lab) for 3D modeling, including a blazingly fast virtual screening capability, was developed. 3D-Lab provides an interface to automatic molecular modeling, like conformer generation, ligand alignments, molecular dockings and simple quantum chemistry protocols. 3D-Lab is designed to be modular, and to facilitate sharing of 3D-information to promote interactions between drug designers. Recent enhancements to our open-source virtual reality tool Molecular Rift are described. The integrated drug-design platform allows drug designers to instantaneously access 3D information and readily apply advanced and automated 3D molecular modeling tasks, with the aim to improve decision-making in drug design projects.

Development and experimental test of support vector machines virtual screening method for searching Src inhibitors from large compound libraries.

PubMed

Han, Bucong; Ma, Xiaohua; Zhao, Ruiying; Zhang, Jingxian; Wei, Xiaona; Liu, Xianghui; Liu, Xin; Zhang, Cunlong; Tan, Chunyan; Jiang, Yuyang; Chen, Yuzong

2012-11-23

Src plays various roles in tumour progression, invasion, metastasis, angiogenesis and survival. It is one of the multiple targets of multi-target kinase inhibitors in clinical uses and trials for the treatment of leukemia and other cancers. These successes and appearances of drug resistance in some patients have raised significant interest and efforts in discovering new Src inhibitors. Various in-silico methods have been used in some of these efforts. It is desirable to explore additional in-silico methods, particularly those capable of searching large compound libraries at high yields and reduced false-hit rates. We evaluated support vector machines (SVM) as virtual screening tools for searching Src inhibitors from large compound libraries. SVM trained and tested by 1,703 inhibitors and 63,318 putative non-inhibitors correctly identified 93.53%~ 95.01% inhibitors and 99.81%~ 99.90% non-inhibitors in 5-fold cross validation studies. SVM trained by 1,703 inhibitors reported before 2011 and 63,318 putative non-inhibitors correctly identified 70.45% of the 44 inhibitors reported since 2011, and predicted as inhibitors 44,843 (0.33%) of 13.56M PubChem, 1,496 (0.89%) of 168 K MDDR, and 719 (7.73%) of 9,305 MDDR compounds similar to the known inhibitors. SVM showed comparable yield and reduced false hit rates in searching large compound libraries compared to the similarity-based and other machine-learning VS methods developed from the same set of training compounds and molecular descriptors. We tested three virtual hits of the same novel scaffold from in-house chemical libraries not reported as Src inhibitor, one of which showed moderate activity. SVM may be potentially explored for searching Src inhibitors from large compound libraries at low false-hit rates.

Monocular display unit for 3D display with correct depth perception

NASA Astrophysics Data System (ADS)

Sakamoto, Kunio; Hosomi, Takashi

2009-11-01

A study of virtual-reality system has been popular and its technology has been applied to medical engineering, educational engineering, a CAD/CAM system and so on. The 3D imaging display system has two types in the presentation method; one is a 3-D display system using a special glasses and the other is the monitor system requiring no special glasses. A liquid crystal display (LCD) recently comes into common use. It is possible for this display unit to provide the same size of displaying area as the image screen on the panel. A display system requiring no special glasses is useful for a 3D TV monitor, but this system has demerit such that the size of a monitor restricts the visual field for displaying images. Thus the conventional display can show only one screen, but it is impossible to enlarge the size of a screen, for example twice. To enlarge the display area, the authors have developed an enlarging method of display area using a mirror. Our extension method enables the observers to show the virtual image plane and to enlarge a screen area twice. In the developed display unit, we made use of an image separating technique using polarized glasses, a parallax barrier or a lenticular lens screen for 3D imaging. The mirror can generate the virtual image plane and it enlarges a screen area twice. Meanwhile the 3D display system using special glasses can also display virtual images over a wide area. In this paper, we present a monocular 3D vision system with accommodation mechanism, which is useful function for perceiving depth.

Virtual screening of mandelate racemase mutants with enhanced activity based on binding energy in the transition state.

PubMed

Gu, Jiali; Liu, Min; Guo, Fei; Xie, Wenping; Lu, Wenqiang; Ye, Lidan; Chen, Zhirong; Yuan, Shenfeng; Yu, Hongwei

2014-02-05

Mandelate racemase (MR) is a promising candidate for the dynamic kinetic resolution of racemates. However, the poor activity of MR towards most of its non-natural substrates limits its widespread application. In this work, a virtual screening method based on the binding energy in the transition state was established to assist in the screening of MR mutants with enhanced catalytic efficiency. Using R-3-chloromandelic acid as a model substrate, a total of 53 mutants were constructed based on rational design in the two rounds of screening. The number of mutants for experimental validation was brought down to 17 by the virtual screening method, among which 14 variants turned out to possess improved catalytic efficiency. The variant V26I/Y54V showed 5.2-fold higher catalytic efficiency (k(cat)/K(m)) towards R-3-chloromandelic acid than that observed for the wild-type enzyme. Using this strategy, mutants were successfully obtained for two other substrates, R-mandelamide and R-2-naphthylglycolate (V26I and V29L, respectively), both with a 2-fold improvement in catalytic efficiency. These results demonstrated that this method could effectively predict the trend of mutational effects on catalysis. Analysis from the energetic and structural assays indicated that the enhanced interactions between the active sites and the substrate in the transition state led to improved catalytic efficiency. It was concluded that this virtual screening method based on the binding energy in the transition state was beneficial in enzyme rational redesign and helped to better understand the catalytic properties of the enzyme. Copyright © 2013 Elsevier Inc. All rights reserved.

Virtual daily living test to screen for mild cognitive impairment using kinematic movement analysis

PubMed Central

Seo, Kyoungwon; Kim, Jae-kwan; Oh, Dong Hoon

2017-01-01

Questionnaires or computer-based tests for assessing activities of daily living are well-known approaches to screen for mild cognitive impairment (MCI). However, questionnaires are subjective and computerized tests only collect simple performance data with conventional input devices such as a mouse and keyboard. This study explored the validity and discriminative power of a virtual daily living test as a new diagnostic approach to assess MCI. Twenty-two healthy controls and 20 patients with MCI were recruited. The virtual daily living test presents two complex daily living tasks in an immersive virtual reality environment. The tasks were conducted based on subject body movements and detailed behavioral data (i.e., kinematic measures) were collected. Performance in both the proposed virtual daily living test and conventional neuropsychological tests for patients with MCI was compared to healthy controls. Kinematic measures considered in this study, such as body movement trajectory, time to completion, and speed, classified patients with MCI from healthy controls, F(8, 33) = 5.648, p < 0.001, η2 = 0.578. When both hand and head speed were employed in conjunction with the immediate free-recall test, a conventional neuropsychological test, the discrimination power for screening MCI was significantly improved to 90% sensitivity and 95.5% specificity (cf. the immediate free-recall test alone has 80% sensitivity and 77.3% specificity). Inclusion of the kinematic measures in screening for MCI significantly improved the classification of patients with MCI compared to the healthy control group, Wilks’ Lambda = 0.451, p < 0.001. PMID:28738088

Using computer-aided drug design and medicinal chemistry strategies in the fight against diabetes.

PubMed

Semighini, Evandro P; Resende, Jonathan A; de Andrade, Peterson; Morais, Pedro A B; Carvalho, Ivone; Taft, Carlton A; Silva, Carlos H T P

2011-04-01

The aim of this work is to present a simple, practical and efficient protocol for drug design, in particular Diabetes, which includes selection of the illness, good choice of a target as well as a bioactive ligand and then usage of various computer aided drug design and medicinal chemistry tools to design novel potential drug candidates in different diseases. We have selected the validated target dipeptidyl peptidase IV (DPP-IV), whose inhibition contributes to reduce glucose levels in type 2 diabetes patients. The most active inhibitor with complex X-ray structure reported was initially extracted from the BindingDB database. By using molecular modification strategies widely used in medicinal chemistry, besides current state-of-the-art tools in drug design (including flexible docking, virtual screening, molecular interaction fields, molecular dynamics, ADME and toxicity predictions), we have proposed 4 novel potential DPP-IV inhibitors with drug properties for Diabetes control, which have been supported and validated by all the computational tools used herewith.

Remote Control and Data Acquisition: A Case Study

NASA Technical Reports Server (NTRS)

DeGennaro, Alfred J.; Wilkinson, R. Allen

2000-01-01

This paper details software tools developed to remotely command experimental apparatus, and to acquire and visualize the associated data in soft real time. The work was undertaken because commercial products failed to meet the needs. This work has identified six key factors intrinsic to development of quality research laboratory software. Capabilities include access to all new instrument functions without any programming or dependence on others to write drivers or virtual instruments, simple full screen text-based experiment configuration and control user interface, months of continuous experiment run-times, order of 1% CPU load for condensed matter physics experiment described here, very little imposition of software tool choices on remote users, and total remote control from anywhere in the world over the Internet or from home on a 56 Kb modem as if the user is sitting in the laboratory. This work yielded a set of simple robust tools that are highly reliable, resource conserving, extensible, and versatile, with a uniform simple interface.

Measurement Tools for the Immersive Visualization Environment: Steps Toward the Virtual Laboratory.

PubMed

Hagedorn, John G; Dunkers, Joy P; Satterfield, Steven G; Peskin, Adele P; Kelso, John T; Terrill, Judith E

2007-01-01

This paper describes a set of tools for performing measurements of objects in a virtual reality based immersive visualization environment. These tools enable the use of the immersive environment as an instrument for extracting quantitative information from data representations that hitherto had be used solely for qualitative examination. We provide, within the virtual environment, ways for the user to analyze and interact with the quantitative data generated. We describe results generated by these methods to obtain dimensional descriptors of tissue engineered medical products. We regard this toolbox as our first step in the implementation of a virtual measurement laboratory within an immersive visualization environment.

Virtual gastrointestinal colonoscopy in combination with large bowel endoscopy: Clinical application

PubMed Central

He, Qing; Rao, Ting; Guan, Yong-Song

2014-01-01

Although colorectal cancer (CRC) has no longer been the leading cancer killer worldwide for years with the exponential development in computed tomography (CT) or magnetic resonance imaging, and positron emission tomography/CT as well as virtual colonoscopy for early detection, the CRC related mortality is still high. The objective of CRC screening is to reduce the burden of CRC and thereby the morbidity and mortality rates of the disease. It is believed that this goal can be achieved by regularly screening the average-risk population, enabling the detection of cancer at early, curable stages, and polyps before they become cancerous. Large-scale screening with multimodality imaging approaches plays an important role in reaching that goal to detect polyps, Crohn’s disease, ulcerative colitis and CRC in early stage. This article reviews kinds of presentative imaging procedures for various screening options and updates detecting, staging and re-staging of CRC patients for determining the optimal therapeutic method and forecasting the risk of CRC recurrence and the overall prognosis. The combination use of virtual colonoscopy and conventional endoscopy, advantages and limitations of these modalities are also discussed. PMID:25320519

Novel design strategy for checkpoint kinase 2 inhibitors using pharmacophore modeling, combinatorial fusion, and virtual screening.

PubMed

Lin, Chun-Yuan; Wang, Yen-Ling

2014-01-01

Checkpoint kinase 2 (Chk2) has a great effect on DNA-damage and plays an important role in response to DNA double-strand breaks and related lesions. In this study, we will concentrate on Chk2 and the purpose is to find the potential inhibitors by the pharmacophore hypotheses (PhModels), combinatorial fusion, and virtual screening techniques. Applying combinatorial fusion into PhModels and virtual screening techniques is a novel design strategy for drug design. We used combinatorial fusion to analyze the prediction results and then obtained the best correlation coefficient of the testing set (r test) with the value 0.816 by combining the Best(train)Best(test) and Fast(train)Fast(test) prediction results. The potential inhibitors were selected from NCI database by screening according to Best(train)Best(test) + Fast(train)Fast(test) prediction results and molecular docking with CDOCKER docking program. Finally, the selected compounds have high interaction energy between a ligand and a receptor. Through these approaches, 23 potential inhibitors for Chk2 are retrieved for further study.

Discovering new PI3Kα inhibitors with a strategy of combining ligand-based and structure-based virtual screening

NASA Astrophysics Data System (ADS)

Yu, Miao; Gu, Qiong; Xu, Jun

2018-02-01

PI3Kα is a promising drug target for cancer chemotherapy. In this paper, we report a strategy of combing ligand-based and structure-based virtual screening to identify new PI3Kα inhibitors. First, naïve Bayesian (NB) learning models and a 3D-QSAR pharmacophore model were built based upon known PI3Kα inhibitors. Then, the SPECS library was screened by the best NB model. This resulted in virtual hits, which were validated by matching the structures against the pharmacophore models. The pharmacophore matched hits were then docked into PI3Kα crystal structures to form ligand-receptor complexes, which are further validated by the Glide-XP program to result in structural validated hits. The structural validated hits were examined by PI3Kα inhibitory assay. With this screening protocol, ten PI3Kα inhibitors with new scaffolds were discovered with IC50 values ranging 0.44-31.25 μM. The binding affinities for the most active compounds 33 and 74 were estimated through molecular dynamics simulations and MM-PBSA analyses.

MISR Center Block Time Tool

Atmospheric Science Data Center

2013-04-01

  MISR Center Block Time Tool The misr_time tool calculates the block center times for MISR Level 1B2 files. This is ... version of the IDL package or by using the IDL Virtual Machine application. The IDL Virtual Machine is bundled with IDL and is ...

Influence of real and virtual heights on standing balance.

PubMed

Cleworth, Taylor W; Horslen, Brian C; Carpenter, Mark G

2012-06-01

Fear and anxiety induced by threatening scenarios, such as standing on elevated surfaces, have been shown to influence postural control in young adults. There is also a need to understand how postural threat influences postural control in populations with balance deficits and risk of falls. However, safety and feasibility issues limit opportunities to place such populations in physically threatening scenarios. Virtual reality (VR) has successfully been used to simulate threatening environments, although it is unclear whether the same postural changes can be elicited by changes in virtual and real threat conditions. Therefore, the purpose of this study was to compare the effects of real and virtual heights on changes to standing postural control, electrodermal activity (EDA) and psycho-social state. Seventeen subjects stood at low and high heights in both real and virtual environments matched in scale and visual detail. A repeated measures ANOVA revealed increases with height, independent of visual environment, in EDA, anxiety, fear, and center of pressure (COP) frequency, and decreases with height in perceived stability, balance confidence and COP amplitude. Interaction effects were seen for fear and COP mean position; where real elicited larger changes with height than VR. This study demonstrates the utility of VR, as simulated heights resulted in changes to postural, autonomic and psycho-social measures similar to those seen at real heights. As a result, VR may be a useful tool for studying threat related changes in postural control in populations at risk of falls, and to screen and rehabilitate balance deficits associated with fear and anxiety. Copyright © 2012 Elsevier B.V. All rights reserved.

G2H--graphics-to-haptic virtual environment development tool for PC's.

PubMed

Acosta, E; Temkin, B; Krummel, T M; Heinrichs, W L

2000-01-01

For surgical training and preparations, the existing surgical virtual environments have shown great improvement. However, these improvements are more in the visual aspect. The incorporation of haptics into virtual reality base surgical simulations would enhance the sense of realism greatly. To aid in the development of the haptic surgical virtual environment we have created a graphics to haptic, G2H, virtual environment developer tool. G2H transforms graphical virtual environments (created or imported) to haptic virtual environments without programming. The G2H capability has been demonstrated using the complex 3D pelvic model of Lucy 2.0, the Stanford Visible Female. The pelvis was made haptic using G2H without any further programming effort.

[Virtual reality simulation training in gynecology: review and perspectives].

PubMed

Ricard-Gauthier, Dominique; Popescu, Silvia; Benmohamed, Naida; Petignat, Patrick; Dubuisson, Jean

2016-10-26

Laparoscopic simulation has rapidly become an important tool for learning and acquiring technical skills in surgery. It is based on two different complementary pedagogic tools : the box model trainer and the virtual reality simulator. The virtual reality simulator has shown its efficiency by improving surgical skills, decreasing operating time, improving economy of movements and improving self-confidence. The main objective of this tool is the opportunity to easily organize a regular, structured and uniformed training program enabling an automated individualized feedback.

Evolution of catalytic centers of antibodies by virtual screening of broad repertoire of mutants using supercomputer.

PubMed

Golovin, A V; Smirnov, I V; Stepanova, A V; Zalevskiy, A O; Zlobin, A S; Ponomarenko, N A; Belogurov, A A; Knorre, V D; Hurs, E N; Chatziefthimiou, S D; Wilmanns, M; Blackburn, G M; Khomutov, R M; Gabibov, A G

2017-07-01

It is proposed to perform quantum mechanical/molecular dynamics calculations of chemical reactions that are planned to be catalyzed by antibodies and then conduct a virtual screening of the library of potential antibody mutants to select an optimal biocatalyst. We tested the effectiveness of this approach by the example of hydrolysis of organophosphorus toxicant paraoxon using kinetic approaches and X-ray analysis of the antibody biocatalyst designed de novo.

Experience in Education Environment Virtualization within the Automated Information System "Platonus" (Kazakhstan)

ERIC Educational Resources Information Center

Abeldina, Zhaidary; Moldumarova, Zhibek; Abeldina, Rauza; Makysh, Gulmira; Moldumarova, Zhuldyz Ilibaevna

2016-01-01

This work reports on the use of virtual tools as means of learning process activation. A good result can be achieved by combining the classical learning with modern computer technology. By creating a virtual learning environment and using multimedia learning tools one can obtain a significant result while facilitating the development of students'…

Attitude and Self-Efficacy Change: English Language Learning in Virtual Worlds

ERIC Educational Resources Information Center

Zheng, Dongping; Young, Michael F.; Brewer, Robert A.; Wagner, Manuela

2009-01-01

This study explored affective factors in learning English as a foreign language in a 3D game-like virtual world, Quest Atlantis (QA). Through the use of communication tools (e.g., chat, bulletin board, telegrams, and email), 3D avatars, and 2D webpage navigation tools in virtual space, nonnative English speakers (NNES) co-solved online…

Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation

PubMed Central

Guasch, Laura; Sala, Esther; Castell-Auví, Anna; Cedó, Lidia; Liedl, Klaus R.; Wolber, Gerhard; Muehlbacher, Markus; Mulero, Miquel; Pinent, Montserrat; Ardévol, Anna; Valls, Cristina; Pujadas, Gerard; Garcia-Vallvé, Santiago

2012-01-01

Background Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural products. Methodology/Principal Findings We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPARγ partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPARγ partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPARγ partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPARγ partial agonists: they bind to PPARγ, do not or only moderately stimulate the transactivation activity of PPARγ, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. Conclusions/Significance We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPARγ partial agonists. PMID:23226391

Comparative Analysis of Virtual Screening Approaches in the Search for Novel EphA2 Receptor Antagonists.

PubMed

Callegari, Donatella; Pala, Daniele; Scalvini, Laura; Tognolini, Massimiliano; Incerti, Matteo; Rivara, Silvia; Mor, Marco; Lodola, Alessio

2015-09-17

The EphA2 receptor and its ephrin-A1 ligand form a key cell communication system, which has been found overexpressed in many cancer types and involved in tumor growth. Recent medicinal chemistry efforts have identified bile acid derivatives as low micromolar binders of the EphA2 receptor. However, these compounds suffer from poor physicochemical properties, hampering their use in vivo. The identification of compounds able to disrupt the EphA2-ephrin-A1 complex lacking the bile acid scaffold may lead to new pharmacological tools suitable for in vivo studies. To identify the most promising virtual screening (VS) protocol aimed at finding novel EphA2 antagonists, we investigated the ability of both ligand-based and structure-based approaches to retrieve known EphA2 antagonists from libraries of decoys with similar molecular properties. While ligand-based VSs were conducted using UniPR129 and ephrin-A1 ligand as reference structures, structure-based VSs were performed with Glide, using the X-ray structure of the EphA2 receptor/ephrin-A1 complex. A comparison of enrichment factors showed that ligand-based approaches outperformed the structure-based ones, suggesting ligand-based methods using the G-H loop of ephrin-A1 ligand as template as the most promising protocols to search for novel EphA2 antagonists.

Applicability of three-dimensional imaging techniques in fetal medicine*

PubMed Central

Werner Júnior, Heron; dos Santos, Jorge Lopes; Belmonte, Simone; Ribeiro, Gerson; Daltro, Pedro; Gasparetto, Emerson Leandro; Marchiori, Edson

2016-01-01

Objective To generate physical models of fetuses from images obtained with three-dimensional ultrasound (3D-US), magnetic resonance imaging (MRI), and, occasionally, computed tomography (CT), in order to guide additive manufacturing technology. Materials and Methods We used 3D-US images of 31 pregnant women, including 5 who were carrying twins. If abnormalities were detected by 3D-US, both MRI and in some cases CT scans were then immediately performed. The images were then exported to a workstation in DICOM format. A single observer performed slice-by-slice manual segmentation using a digital high resolution screen. Virtual 3D models were obtained from software that converts medical images into numerical models. Those models were then generated in physical form through the use of additive manufacturing techniques. Results Physical models based upon 3D-US, MRI, and CT images were successfully generated. The postnatal appearance of either the aborted fetus or the neonate closely resembled the physical models, particularly in cases of malformations. Conclusion The combined use of 3D-US, MRI, and CT could help improve our understanding of fetal anatomy. These three screening modalities can be used for educational purposes and as tools to enable parents to visualize their unborn baby. The images can be segmented and then applied, separately or jointly, in order to construct virtual and physical 3D models. PMID:27818540

FTree query construction for virtual screening: a statistical analysis.

PubMed

Gerlach, Christof; Broughton, Howard; Zaliani, Andrea

2008-02-01

FTrees (FT) is a known chemoinformatic tool able to condense molecular descriptions into a graph object and to search for actives in large databases using graph similarity. The query graph is classically derived from a known active molecule, or a set of actives, for which a similar compound has to be found. Recently, FT similarity has been extended to fragment space, widening its capabilities. If a user were able to build a knowledge-based FT query from information other than a known active structure, the similarity search could be combined with other, normally separate, fields like de-novo design or pharmacophore searches. With this aim in mind, we performed a comprehensive analysis of several databases in terms of FT description and provide a basic statistical analysis of the FT spaces so far at hand. Vendors' catalogue collections and MDDR as a source of potential or known "actives", respectively, have been used. With the results reported herein, a set of ranges, mean values and standard deviations for several query parameters are presented in order to set a reference guide for the users. Applications on how to use this information in FT query building are also provided, using a newly built 3D-pharmacophore from 57 5HT-1F agonists and a published one which was used for virtual screening for tRNA-guanine transglycosylase (TGT) inhibitors.

Physics-based scoring of protein-ligand interactions: explicit polarizability, quantum mechanics and free energies.

PubMed

Bryce, Richard A

2011-04-01

The ability to accurately predict the interaction of a ligand with its receptor is a key limitation in computer-aided drug design approaches such as virtual screening and de novo design. In this article, we examine current strategies for a physics-based approach to scoring of protein-ligand affinity, as well as outlining recent developments in force fields and quantum chemical techniques. We also consider advances in the development and application of simulation-based free energy methods to study protein-ligand interactions. Fuelled by recent advances in computational algorithms and hardware, there is the opportunity for increased integration of physics-based scoring approaches at earlier stages in computationally guided drug discovery. Specifically, we envisage increased use of implicit solvent models and simulation-based scoring methods as tools for computing the affinities of large virtual ligand libraries. Approaches based on end point simulations and reference potentials allow the application of more advanced potential energy functions to prediction of protein-ligand binding affinities. Comprehensive evaluation of polarizable force fields and quantum mechanical (QM)/molecular mechanical and QM methods in scoring of protein-ligand interactions is required, particularly in their ability to address challenging targets such as metalloproteins and other proteins that make highly polar interactions. Finally, we anticipate increasingly quantitative free energy perturbation and thermodynamic integration methods that are practical for optimization of hits obtained from screened ligand libraries.

FTree query construction for virtual screening: a statistical analysis

NASA Astrophysics Data System (ADS)

Gerlach, Christof; Broughton, Howard; Zaliani, Andrea

2008-02-01

FTrees (FT) is a known chemoinformatic tool able to condense molecular descriptions into a graph object and to search for actives in large databases using graph similarity. The query graph is classically derived from a known active molecule, or a set of actives, for which a similar compound has to be found. Recently, FT similarity has been extended to fragment space, widening its capabilities. If a user were able to build a knowledge-based FT query from information other than a known active structure, the similarity search could be combined with other, normally separate, fields like de-novo design or pharmacophore searches. With this aim in mind, we performed a comprehensive analysis of several databases in terms of FT description and provide a basic statistical analysis of the FT spaces so far at hand. Vendors' catalogue collections and MDDR as a source of potential or known "actives", respectively, have been used. With the results reported herein, a set of ranges, mean values and standard deviations for several query parameters are presented in order to set a reference guide for the users. Applications on how to use this information in FT query building are also provided, using a newly built 3D-pharmacophore from 57 5HT-1F agonists and a published one which was used for virtual screening for tRNA-guanine transglycosylase (TGT) inhibitors.

Open-source platform to benchmark fingerprints for ligand-based virtual screening

PubMed Central

2013-01-01

Similarity-search methods using molecular fingerprints are an important tool for ligand-based virtual screening. A huge variety of fingerprints exist and their performance, usually assessed in retrospective benchmarking studies using data sets with known actives and known or assumed inactives, depends largely on the validation data sets used and the similarity measure used. Comparing new methods to existing ones in any systematic way is rather difficult due to the lack of standard data sets and evaluation procedures. Here, we present a standard platform for the benchmarking of 2D fingerprints. The open-source platform contains all source code, structural data for the actives and inactives used (drawn from three publicly available collections of data sets), and lists of randomly selected query molecules to be used for statistically valid comparisons of methods. This allows the exact reproduction and comparison of results for future studies. The results for 12 standard fingerprints together with two simple baseline fingerprints assessed by seven evaluation methods are shown together with the correlations between methods. High correlations were found between the 12 fingerprints and a careful statistical analysis showed that only the two baseline fingerprints were different from the others in a statistically significant way. High correlations were also found between six of the seven evaluation methods, indicating that despite their seeming differences, many of these methods are similar to each other. PMID:23721588

Evaluation of a focused virtual library of heterobifunctional ligands for Clostridium difficile toxins.

PubMed

Sanhueza, Carlos A; Cartmell, Jonathan; El-Hawiet, Amr; Szpacenko, Adam; Kitova, Elena N; Daneshfar, Rambod; Klassen, John S; Lang, Dean E; Eugenio, Luiz; Ng, Kenneth K-S; Kitov, Pavel I; Bundle, David R

2015-01-07

A focused library of virtual heterobifunctional ligands was generated in silico and a set of ligands with recombined fragments was synthesized and evaluated for binding to Clostridium difficile toxins. The position of the trisaccharide fragment was used as a reference for filtering docked poses during virtual screening to match the trisaccharide ligand in a crystal structure. The peptoid, a diversity fragment probing the protein surface area adjacent to a known binding site, was generated by a multi-component Ugi reaction. Our approach combines modular fragment-based design with in silico screening of synthetically feasible compounds and lays the groundwork for future efforts in development of composite bifunctional ligands for large clostridial toxins.

Teaching Web Security Using Portable Virtual Labs

ERIC Educational Resources Information Center

Chen, Li-Chiou; Tao, Lixin

2012-01-01

We have developed a tool called Secure WEb dEvelopment Teaching (SWEET) to introduce security concepts and practices for web application development. This tool provides introductory tutorials, teaching modules utilizing virtualized hands-on exercises, and project ideas in web application security. In addition, the tool provides pre-configured…

Virtual Beach: Decision Support Tools for Beach Pathogen Prediction

EPA Science Inventory

The Virtual Beach Managers Tool (VB) is decision-making software developed to help local beach managers make decisions as to when beaches should be closed due to predicted high levels of water borne pathogens. The tool is being developed under the umbrella of EPA's Advanced Monit...

Virtual reality skills training for health care professionals in alcohol screening and brief intervention.

PubMed

Fleming, Michael; Olsen, Dale; Stathes, Hilary; Boteler, Laura; Grossberg, Paul; Pfeifer, Judie; Schiro, Stephanie; Banning, Jane; Skochelak, Susan

2009-01-01

Educating physicians and other health care professionals about the identification and treatment of patients who drink more than recommended limits is an ongoing challenge. An educational randomized controlled trial was conducted to test the ability of a stand-alone training simulation to improve the clinical skills of health care professionals in alcohol screening and intervention. The "virtual reality simulation" combined video, voice recognition, and nonbranching logic to create an interactive environment that allowed trainees to encounter complex social cues and realistic interpersonal exchanges. The simulation included 707 questions and statements and 1207 simulated patient responses. A sample of 102 health care professionals (10 physicians; 30 physician assistants or nurse practitioners; 36 medical students; 26 pharmacy, physican assistant, or nurse practitioner students) were randomly assigned to a no training group (n = 51) or a computer-based virtual reality intervention (n = 51). Professionals in both groups had similar pretest standardized patient alcohol screening skill scores: 53.2 (experimental) vs 54.4 (controls), 52.2 vs 53.7 alcohol brief intervention skills, and 42.9 vs 43.5 alcohol referral skills. After repeated practice with the simulation there were significant increases in the scores of the experimental group at 6 months after randomization compared with the control group for the screening (67.7 vs 58.1; P < .001) and brief intervention (58.3 vs 51.6; P < .04) scenarios. The technology tested in this trial is the first virtual reality simulation to demonstrate an increase in the alcohol screening and brief intervention skills of health care professionals.

Virtual Reality Skills Training for Health Care Professionals in Alcohol Screening and Brief Intervention

PubMed Central

Fleming, Michael; Olsen, Dale; Stathes, Hilary; Boteler, Laura; Grossberg, Paul; Pfeifer, Judie; Schiro, Stephanie; Banning, Jane; Skochelak, Susan

2009-01-01

Background Educating physicians and other health care professionals to identify and treat patients who drink above recommended limits is an ongoing challenge. Methods An educational Randomized Control Trial (RCT) was conducted to test the ability of a stand alone training simulation to improve the clinical skills of health care professionals in alcohol screening and intervention. The “virtual reality simulation” combines video, voice recognition and non branching logic to create an interactive environment that allows trainees to encounter complex social cues and realistic interpersonal exchanges. The simulation includes 707 questions and statements and 1207 simulated patient responses. Results A sample of 102 health care professionals (10 physicians; 30 physician assistants [PAs] or nurse practitioners [NPs]; 36 medical students; 26 pharmacy, PA or NP students) were randomly assigned to no training (n=51) or a computer based virtual reality intervention (n=51). Subjects in both groups had similar pre-test standardized patient alcohol screening skill scores – 53.2 (experimental) vs. 54.4 (controls), 52.2 vs. 53.7 alcohol brief intervention skills, and 42.9 vs. 43.5 alcohol referral skills. Following repeated practice with the simulation there were significant increases in the scores of the experimental group at 6 months post-randomization compared to the control group for the screening (67.7 vs. 58.1, p<.001) and brief intervention (58.3 vs. 51.6, p<.04) scenarios. Conclusions The technology tested in this trial is the first virtual reality simulation to demonstrate an increase in the alcohol screening and brief intervention skills of health care professionals. PMID:19587253

Uniqueness of Experience and Virtual Playworlds: Playing Is Not Just for Fun

ERIC Educational Resources Information Center

Talamo, Alessandra; Pozzi, Simone; Mellini, Barbara

2010-01-01

Social interactions within virtual communities are often described solely as being online experiences. Such descriptions are limited, for they fail to reference life external to the screen. The terms "virtual" and "real" have a negative connotation for many people and can even be interpreted to mean that something is "false" or "inauthentic."…

Spectrophores as one-dimensional descriptors calculated from three-dimensional atomic properties: applications ranging from scaffold hopping to multi-target virtual screening.

PubMed

Gladysz, Rafaela; Dos Santos, Fabio Mendes; Langenaeker, Wilfried; Thijs, Gert; Augustyns, Koen; De Winter, Hans

2018-03-07

Spectrophores are novel descriptors that are calculated from the three-dimensional atomic properties of molecules. In our current implementation, the atomic properties that were used to calculate spectrophores include atomic partial charges, atomic lipophilicity indices, atomic shape deviations and atomic softness properties. This approach can easily be widened to also include additional atomic properties. Our novel methodology finds its roots in the experimental affinity fingerprinting technology developed in the 1990's by Terrapin Technologies. Here we have translated it into a purely virtual approach using artificial affinity cages and a simplified metric to calculate the interaction between these cages and the atomic properties. A typical spectrophore consists of a vector of 48 real numbers. This makes it highly suitable for the calculation of a wide range of similarity measures for use in virtual screening and for the investigation of quantitative structure-activity relationships in combination with advanced statistical approaches such as self-organizing maps, support vector machines and neural networks. In our present report we demonstrate the applicability of our novel methodology for scaffold hopping as well as virtual screening.

Optimal affinity ranking for automated virtual screening validated in prospective D3R grand challenges

NASA Astrophysics Data System (ADS)

Wingert, Bentley M.; Oerlemans, Rick; Camacho, Carlos J.

2018-01-01

The goal of virtual screening is to generate a substantially reduced and enriched subset of compounds from a large virtual chemistry space. Critical in these efforts are methods to properly rank the binding affinity of compounds. Prospective evaluations of ranking strategies in the D3R grand challenges show that for targets with deep pockets the best correlations (Spearman ρ 0.5) were obtained by our submissions that docked compounds to the holo-receptors with the most chemically similar ligand. On the other hand, for targets with open pockets using multiple receptor structures is not a good strategy. Instead, docking to a single optimal receptor led to the best correlations (Spearman ρ 0.5), and overall performs better than any other method. Yet, choosing a suboptimal receptor for crossdocking can significantly undermine the affinity rankings. Our submissions that evaluated the free energy of congeneric compounds were also among the best in the community experiment. Error bars of around 1 kcal/mol are still too large to significantly improve the overall rankings. Collectively, our top of the line predictions show that automated virtual screening with rigid receptors perform better than flexible docking and other more complex methods.

Discovery of Novel New Delhi Metallo-β-Lactamases-1 Inhibitors by Multistep Virtual Screening

PubMed Central

Wang, Xuequan; Lu, Meiling; Shi, Yang; Ou, Yu; Cheng, Xiaodong

2015-01-01

The emergence of NDM-1 containing multi-antibiotic resistant "Superbugs" necessitates the needs of developing of novel NDM-1inhibitors. In this study, we report the discovery of novel NDM-1 inhibitors by multi-step virtual screening. From a 2,800,000 virtual drug-like compound library selected from the ZINC database, we generated a focused NDM-1 inhibitor library containing 298 compounds of which 44 chemical compounds were purchased and evaluated experimentally for their ability to inhibit NDM-1 in vitro. Three novel NDM-1 inhibitors with micromolar IC50 values were validated. The most potent inhibitor, VNI-41, inhibited NDM-1 with an IC50 of 29.6 ± 1.3 μM. Molecular dynamic simulation revealed that VNI-41 interacted extensively with the active site. In particular, the sulfonamide group of VNI-41 interacts directly with the metal ion Zn1 that is critical for the catalysis. These results demonstrate the feasibility of applying virtual screening methodologies in identifying novel inhibitors for NDM-1, a metallo-β-lactamase with a malleable active site and provide a mechanism base for rational design of NDM-1 inhibitors using sulfonamide as a functional scaffold. PMID:25734558

A model for flexible tools used in minimally invasive medical virtual environments.

PubMed

Soler, Francisco; Luzon, M Victoria; Pop, Serban R; Hughes, Chris J; John, Nigel W; Torres, Juan Carlos

2011-01-01

Within the limits of current technology, many applications of a virtual environment will trade-off accuracy for speed. This is not an acceptable compromise in a medical training application where both are essential. Efficient algorithms must therefore be developed. The purpose of this project is the development and validation of a novel physics-based real time tool manipulation model, which is easy to integrate into any medical virtual environment that requires support for the insertion of long flexible tools into complex geometries. This encompasses medical specialities such as vascular interventional radiology, endoscopy, and laparoscopy, where training, prototyping of new instruments/tools and mission rehearsal can all be facilitated by using an immersive medical virtual environment. Our model recognises and uses accurately patient specific data and adapts to the geometrical complexity of the vessel in real time.

Learning Rationales and Virtual Reality Technology in Education.

ERIC Educational Resources Information Center

Chiou, Guey-Fa

1995-01-01

Defines and describes virtual reality technology and differentiates between virtual learning environment, learning material, and learning tools. Links learning rationales to virtual reality technology to pave conceptual foundations for application of virtual reality technology education. Constructivism, case-based learning, problem-based learning,…

Astronomical virtual observatory and the place and role of Bulgarian one

NASA Astrophysics Data System (ADS)

Petrov, Georgi; Dechev, Momchil; Slavcheva-Mihova, Luba; Duchlev, Peter; Mihov, Bojko; Kochev, Valentin; Bachev, Rumen

2009-07-01

Virtual observatory could be defined as a collection of integrated astronomical data archives and software tools that utilize computer networks to create an environment in which research can be conducted. Several countries have initiated national virtual observatory programs that combine existing databases from ground-based and orbiting observatories, scientific facility especially equipped to detect and record naturally occurring scientific phenomena. As a result, data from all the world's major observatories will be available to all users and to the public. This is significant not only because of the immense volume of astronomical data but also because the data on stars and galaxies has been compiled from observations in a variety of wavelengths-optical, radio, infrared, gamma ray, X-ray and more. In a virtual observatory environment, all of this data is integrated so that it can be synthesized and used in a given study. During the autumn of the 2001 (26.09.2001) six organizations from Europe put the establishment of the Astronomical Virtual Observatory (AVO)-ESO, ESA, Astrogrid, CDS, CNRS, Jodrell Bank (Dolensky et al., 2003). Its aims have been outlined as follows: - To provide comparative analysis of large sets of multiwavelength data; - To reuse data collected by a single source; - To provide uniform access to data; - To make data available to less-advantaged communities; - To be an educational tool. The Virtual observatory includes: - Tools that make it easy to locate and retrieve data from catalogues, archives, and databases worldwide; - Tools for data analysis, simulation, and visualization; - Tools to compare observations with results obtained from models, simulations and theory; - Interoperability: services that can be used regardless of the clients computing platform, operating system and software capabilities; - Access to data in near real-time, archived data and historical data; - Additional information - documentation, user-guides, reports, publications, news and so on. This large growth of astronomical data and the necessity of an easy access to those data led to the foundation of the International Virtual Observatory Alliance (IVOA). IVOA was formed in June 2002. By January 2005, the IVOA has grown to include 15 funded VO projects from Australia, Canada, China, Europe, France, Germany, Hungary, India, Italy, Japan, Korea, Russia, Spain, the United Kingdom, and the United States. At the time being Bulgaria is not a member of European Astronomical Virtual Observatory and as the Bulgarian Virtual Observatory is not a legal entity, we are not members of IVOA. The main purpose of the project is Bulgarian Virtual Observatory to join the leading virtual astronomical institutions in the world. Initially the Bulgarian Virtual Observatory will include: - BG Galaxian virtual observatory; - BG Solar virtual observatory; - Department Star clusters of IA, BAS; - WFPDB group of IA, BAS. All available data will be integrated in the Bulgarian centers of astronomical data, conducted by the Wide Field Plate Archive data centre. For the above purpose POSTGRESQL or/and MySQL will be installed on the server of BG-VO and SAADA tools, ESO-MEX or/and DAL ToolKit to transform our FITS files in standard format for VO-tools. A part of the participants was acquainted with the principles of these products during the "Days of virtual observatory in Sofia" January, 2008.

Tools for Teaching Virtual Teams: A Comparative Resource Review

ERIC Educational Resources Information Center

Larson, Barbara; Leung, Opal; Mullane, Kenneth

2017-01-01

As the ubiquity of virtual work--and particularly virtual project teams--increases in the professional environment, management and other professional programs are increasingly teaching students skills related to virtual work. One of the most common forms of teaching virtual work skills is a virtual team project, in which students collaborate with…

American Medical Society for Sports Medicine

MedlinePlus

... Research Grants Virtual Journal Club Resources Research Awards Research Survey Requests ADVOCACY ADVOCACY Practice Tools Issue Briefs State ... Research Grants Virtual Journal Club Resources Research Awards Research Survey Requests Advocacy Advocacy Practice Tools Issue Briefs State ...

vSDC: a method to improve early recognition in virtual screening when limited experimental resources are available.

PubMed

Chaput, Ludovic; Martinez-Sanz, Juan; Quiniou, Eric; Rigolet, Pascal; Saettel, Nicolas; Mouawad, Liliane

2016-01-01

In drug design, one may be confronted to the problem of finding hits for targets for which no small inhibiting molecules are known and only low-throughput experiments are available (like ITC or NMR studies), two common difficulties encountered in a typical academic setting. Using a virtual screening strategy like docking can alleviate some of the problems and save a considerable amount of time by selecting only top-ranking molecules, but only if the method is very efficient, i.e. when a good proportion of actives are found in the 1-10 % best ranked molecules. The use of several programs (in our study, Gold, Surflex, FlexX and Glide were considered) shows a divergence of the results, which presents a difficulty in guiding the experiments. To overcome this divergence and increase the yield of the virtual screening, we created the standard deviation consensus (SDC) and variable SDC (vSDC) methods, consisting of the intersection of molecule sets from several virtual screening programs, based on the standard deviations of their ranking distributions. SDC allowed us to find hits for two new protein targets by testing only 9 and 11 small molecules from a chemical library of circa 15,000 compounds. Furthermore, vSDC, when applied to the 102 proteins of the DUD-E benchmarking database, succeeded in finding more hits than any of the four isolated programs for 13-60 % of the targets. In addition, when only 10 molecules of each of the 102 chemical libraries were considered, vSDC performed better in the number of hits found, with an improvement of 6-24 % over the 10 best-ranked molecules given by the individual docking programs.Graphical abstractIn drug design, for a given target and a given chemical library, the results obtained with different virtual screening programs are divergent. So how to rationally guide the experimental tests, especially when only a few number of experiments can be made? The variable Standard Deviation Consensus (vSDC) method was developed to answer this issue. Left panel the vSDC principle consists of intersecting molecule sets, chosen on the basis of the standard deviations of their ranking distributions, obtained from various virtual screening programs. In this study Glide, Gold, FlexX and Surflex were used and tested on the 102 targets of the DUD-E database. Right panel Comparison of the average percentage of hits found with vSDC and each of the four programs, when only 10 molecules from each of the 102 chemical libraries of the DUD-E database were considered. On average, vSDC was capable of finding 38 % of the findable hits, against 34 % for Glide, 32 % for Gold, 16 % for FlexX and 14 % for Surflex, showing that with vSDC, it was possible to overcome the unpredictability of the virtual screening results and to improve them.

Complete genome-wide screening and subtractive genomic approach revealed new virulence factors, potential drug targets against bio-war pathogen Brucella melitensis 16M

PubMed Central

Pradeepkiran, Jangampalli Adi; Sainath, Sri Bhashyam; Kumar, Konidala Kranthi; Bhaskar, Matcha

2015-01-01

Brucella melitensis 16M is a Gram-negative coccobacillus that infects both animals and humans. It causes a disease known as brucellosis, which is characterized by acute febrile illness in humans and causes abortions in livestock. To prevent and control brucellosis, identification of putative drug targets is crucial. The present study aimed to identify drug targets in B. melitensis 16M by using a subtractive genomic approach. We used available database repositories (Database of Essential Genes, Kyoto Encyclopedia of Genes and Genomes Automatic Annotation Server, and Kyoto Encyclopedia of Genes and Genomes) to identify putative genes that are nonhomologous to humans and essential for pathogen B. melitensis 16M. The results revealed that among 3 Mb genome size of pathogen, 53 putative characterized and 13 uncharacterized hypothetical genes were identified; further, from Basic Local Alignment Search Tool protein analysis, one hypothetical protein showed a close resemblance (50%) to Silicibacter pomeroyi DUF1285 family protein (2RE3). A further homology model of the target was constructed using MODELLER 9.12 and optimized through variable target function method by molecular dynamics optimization with simulating annealing. The stereochemical quality of the restrained model was evaluated by PROCHECK, VERIFY-3D, ERRAT, and WHATIF servers. Furthermore, structure-based virtual screening was carried out against the predicted active site of the respective protein using the glycerol structural analogs from the PubChem database. We identified five best inhibitors with strong affinities, stable interactions, and also with reliable drug-like properties. Hence, these leads might be used as the most effective inhibitors of modeled protein. The outcome of the present work of virtual screening of putative gene targets might facilitate design of potential drugs for better treatment against brucellosis. PMID:25834405

Homoharringtonine targets Smad3 and TGF-β pathway to inhibit the proliferation of acute myeloid leukemia cells.

PubMed

Chen, Jian; Mu, Qitian; Li, Xia; Yin, Xiufeng; Yu, Mengxia; Jin, Jing; Li, Chenying; Zhou, Yile; Zhou, Jiani; Suo, Shanshan; Lu, Demin; Jin, Jie

2017-06-20

Homoharringtonine (HHT) has long and widely been used in China for the treatment of acute myeloid leukemia (AML), the clinical therapeutic effect is significant but the working mechanism is poorly understood. The purpose of this study is to screen the possible target for HHT with virtual screening and verify the findings by cell experiments. Software including Autodock, Python, and MGL tools were used, with HHT being the ligand and proteins from PI3K-Akt pathway, Jak-stat pathway, TGF-β pathway and NK-κB pathway as the receptors. Human AML cell lines including U937, KG-1, THP-1 were cultured and used as the experiment cell lines. MTT assay was used for proliferation detection, flowcytometry was used to detect apoptosis and cell cycle arrest upon HHT functioning, western blotting was used to detect the protein level changes, viral shRNA transfection was used to suppress the expression level of the target protein candidate, and viral mRNA transfection was used for over-expression. Virtual screening revealed that smad3 from TGF-β pathway might be the candidate for HHT binding. In AML cell line U937 and KG-1, HHT can induce the Ser423/425 phosphorylation of smad3, and this phosphorylation can subsequently activate the TGF-β pathway, causing cell cycle arrest at G1 phase in U937 cells and apoptosis in KG-1 cells, knockdown of smad3 can impair the sensitivity of U937 cell to HHT, and over-expression of smad3 can re-establish the sensitivity in both cell lines. We conclude that smad3 is the probable target protein of HHT and plays an important role in the functioning mechanism of HHT.

Homoharringtonine targets Smad3 and TGF-β pathway to inhibit the proliferation of acute myeloid leukemia cells

PubMed Central

Yin, Xiufeng; Yu, Mengxia; Jin, Jing; Li, Chenying; Zhou, Yile; Zhou, Jiani; Suo, Shanshan; Lu, Demin; Jin, Jie

2017-01-01

Homoharringtonine (HHT) has long and widely been used in China for the treatment of acute myeloid leukemia (AML), the clinical therapeutic effect is significant but the working mechanism is poorly understood. The purpose of this study is to screen the possible target for HHT with virtual screening and verify the findings by cell experiments. Software including Autodock, Python, and MGL tools were used, with HHT being the ligand and proteins from PI3K-Akt pathway, Jak-stat pathway, TGF-β pathway and NK-κB pathway as the receptors. Human AML cell lines including U937, KG-1, THP-1 were cultured and used as the experiment cell lines. MTT assay was used for proliferation detection, flowcytometry was used to detect apoptosis and cell cycle arrest upon HHT functioning, western blotting was used to detect the protein level changes, viral shRNA transfection was used to suppress the expression level of the target protein candidate, and viral mRNA transfection was used for over-expression. Virtual screening revealed that smad3 from TGF-β pathway might be the candidate for HHT binding. In AML cell line U937 and KG-1, HHT can induce the Ser423/425 phosphorylation of smad3, and this phosphorylation can subsequently activate the TGF-β pathway, causing cell cycle arrest at G1 phase in U937 cells and apoptosis in KG-1 cells, knockdown of smad3 can impair the sensitivity of U937 cell to HHT, and over-expression of smad3 can re-establish the sensitivity in both cell lines. We conclude that smad3 is the probable target protein of HHT and plays an important role in the functioning mechanism of HHT. PMID:28454099

Discussing Virtual Tools that Simulate Probabilities: What Are the Middle School Teachers' Concerns?

ERIC Educational Resources Information Center

Savard, Annie; Freiman, Viktor; Theis, Laurent; Larose, Fançois

2013-01-01

Mathematics teachers, researchers and specialists in educational technology from Quebec, Canada developed virtual tools that make interactive simulations of games of chance. These tools were presented to a group of teachers from New Brunswick through workshops and they then got to test and validate them with their students. Semi-structured…

Journey to the centre of the cell: Virtual reality immersion into scientific data.

PubMed

Johnston, Angus P R; Rae, James; Ariotti, Nicholas; Bailey, Benjamin; Lilja, Andrew; Webb, Robyn; Ferguson, Charles; Maher, Sheryl; Davis, Thomas P; Webb, Richard I; McGhee, John; Parton, Robert G

2018-02-01

Visualization of scientific data is crucial not only for scientific discovery but also to communicate science and medicine to both experts and a general audience. Until recently, we have been limited to visualizing the three-dimensional (3D) world of biology in 2 dimensions. Renderings of 3D cells are still traditionally displayed using two-dimensional (2D) media, such as on a computer screen or paper. However, the advent of consumer grade virtual reality (VR) headsets such as Oculus Rift and HTC Vive means it is now possible to visualize and interact with scientific data in a 3D virtual world. In addition, new microscopic methods provide an unprecedented opportunity to obtain new 3D data sets. In this perspective article, we highlight how we have used cutting edge imaging techniques to build a 3D virtual model of a cell from serial block-face scanning electron microscope (SBEM) imaging data. This model allows scientists, students and members of the public to explore and interact with a "real" cell. Early testing of this immersive environment indicates a significant improvement in students' understanding of cellular processes and points to a new future of learning and public engagement. In addition, we speculate that VR can become a new tool for researchers studying cellular architecture and processes by populating VR models with molecular data. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

FAF-Drugs2: free ADME/tox filtering tool to assist drug discovery and chemical biology projects.

PubMed

Lagorce, David; Sperandio, Olivier; Galons, Hervé; Miteva, Maria A; Villoutreix, Bruno O

2008-09-24

Drug discovery and chemical biology are exceedingly complex and demanding enterprises. In recent years there are been increasing awareness about the importance of predicting/optimizing the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of small chemical compounds along the search process rather than at the final stages. Fast methods for evaluating ADMET properties of small molecules often involve applying a set of simple empirical rules (educated guesses) and as such, compound collections' property profiling can be performed in silico. Clearly, these rules cannot assess the full complexity of the human body but can provide valuable information and assist decision-making. This paper presents FAF-Drugs2, a free adaptable tool for ADMET filtering of electronic compound collections. FAF-Drugs2 is a command line utility program (e.g., written in Python) based on the open source chemistry toolkit OpenBabel, which performs various physicochemical calculations, identifies key functional groups, some toxic and unstable molecules/functional groups. In addition to filtered collections, FAF-Drugs2 can provide, via Gnuplot, several distribution diagrams of major physicochemical properties of the screened compound libraries. We have developed FAF-Drugs2 to facilitate compound collection preparation, prior to (or after) experimental screening or virtual screening computations. Users can select to apply various filtering thresholds and add rules as needed for a given project. As it stands, FAF-Drugs2 implements numerous filtering rules (23 physicochemical rules and 204 substructure searching rules) that can be easily tuned.

Discovery of d-amino acid oxidase inhibitors based on virtual screening against the lid-open enzyme conformation.

PubMed

Szilágyi, Bence; Skok, Žiga; Rácz, Anita; Frlan, Rok; Ferenczy, György G; Ilaš, Janez; Keserű, György M

2018-06-01

d-Amino acid oxidase (DAAO) inhibitors are typically small polar compounds with often suboptimal pharmacokinetic properties. Features of the native binding site limit the operational freedom of further medicinal chemistry efforts. We therefore initiated a structure based virtual screening campaign based on the X-ray structures of DAAO complexes where larger ligands shifted the loop (lid opening) covering the native binding site. The virtual screening of our in-house collection followed by the in vitro test of the best ranked compounds led to the identification of a new scaffold with micromolar IC 50 . Subsequent SAR explorations enabled us to identify submicromolar inhibitors. Docking studies supported by in vitro activity measurements suggest that compounds bind to the active site with a salt-bridge characteristic to DAAO inhibitor binding. In addition, displacement of and interaction with the loop covering the active site contributes significantly to the activity of the most potent compounds. Copyright © 2018 Elsevier Ltd. All rights reserved.

The power metric: a new statistically robust enrichment-type metric for virtual screening applications with early recovery capability.

PubMed

Lopes, Julio Cesar Dias; Dos Santos, Fábio Mendes; Martins-José, Andrelly; Augustyns, Koen; De Winter, Hans

2017-01-01

A new metric for the evaluation of model performance in the field of virtual screening and quantitative structure-activity relationship applications is described. This metric has been termed the power metric and is defined as the fraction of the true positive rate divided by the sum of the true positive and false positive rates, for a given cutoff threshold. The performance of this metric is compared with alternative metrics such as the enrichment factor, the relative enrichment factor, the receiver operating curve enrichment factor, the correct classification rate, Matthews correlation coefficient and Cohen's kappa coefficient. The performance of this new metric is found to be quite robust with respect to variations in the applied cutoff threshold and ratio of the number of active compounds to the total number of compounds, and at the same time being sensitive to variations in model quality. It possesses the correct characteristics for its application in early-recognition virtual screening problems.

Combination of virtual screening protocol by in silico towards the discovery of novel 4-hydroxyphenylpyruvate dioxygenase inhibitors

NASA Astrophysics Data System (ADS)

Fu, Ying; Sun, Yi-Na; Yi, Ke-Han; Li, Ming-Qiang; Cao, Hai-Feng; Li, Jia-Zhong; Ye, Fei

2018-02-01

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is a potent new bleaching herbicide target. Therefore, in silico structure-based virtual screening was performed in order to speed up the identification of promising HPPD inhibitors. In this study, an integrated virtual screening protocol by combining 3D-pharmacophore model, molecular docking and molecular dynamics (MD) simulation was established to find novel HPPD inhibitors from four commercial databases. 3D-pharmacophore Hypo1 model was applied to efficiently narrow potential hits. The hit compounds were subsequently submitted to molecular docking studies, showing four compounds as potent inhibitor with the mechanism of the Fe(II) coordination and interaction with Phe360, Phe403 and Phe398. MD result demonstrated that nonpolar term of compound 3881 made great contributions to binding affinities. It showed an IC50 being 2.49 µM against AtHPPD in vitro. The results provided useful information for developing novel HPPD inhibitors, leading to further understanding of the interaction mechanism of HPPD inhibitors.

Docking and scoring with ICM: the benchmarking results and strategies for improvement

PubMed Central

Neves, Marco A. C.; Totrov, Maxim; Abagyan, Ruben

2012-01-01

Flexible docking and scoring using the Internal Coordinate Mechanics software (ICM) was benchmarked for ligand binding mode prediction against the 85 co-crystal structures in the modified Astex data set. The ICM virtual ligand screening was tested against the 40 DUD target benchmarks and 11-target WOMBAT sets. The self-docking accuracy was evaluated for the top 1 and top 3 scoring poses at each ligand binding site with near native conformations below 2 Å RMSD found in 91% and 95% of the predictions, respectively. The virtual ligand screening using single rigid pocket conformations provided the median area under the ROC curves equal to 69.4 with 22.0% true positives recovered at 2% false positive rate. Significant improvements up to ROC AUC= 82.2 and ROC(2%)= 45.2 were achieved following our best practices for flexible pocket refinement and out-of-pocket binding rescore. The virtual screening can be further improved by considering multiple conformations of the target. PMID:22569591

Enhancing the Sensitivity of Pharmacophore-Based Virtual Screening by Incorporating Customized ZBG Features: A Case Study Using Histone Deacetylase 8.

PubMed

Hou, Xuben; Du, Jintong; Liu, Renshuai; Zhou, Yi; Li, Minyong; Xu, Wenfang; Fang, Hao

2015-04-27

As key regulators of epigenetic regulation, human histone deacetylases (HDACs) have been identified as drug targets for the treatment of several cancers. The proper recognition of zinc-binding groups (ZBGs) will help improve the accuracy of virtual screening for novel HDAC inhibitors. Here, we developed a high-specificity ZBG-based pharmacophore model for HDAC8 inhibitors by incorporating customized ZBG features. Subsequently, pharmacophore-based virtual screening led to the discovery of three novel HDAC8 inhibitors with low micromole IC50 values (1.8-1.9 μM). Further studies demonstrated that compound H8-A5 was selective for HDAC8 over HDAC 1/4 and showed antiproliferation activity in MDA-MB-231 cancer cells. Molecular docking and molecular dynamic studies suggested a possible binding mode for H8-A5, which provides a good starting point for the development of HDAC8 inhibitors in cancer treatment.

Discovery of new erbB4 inhibitors: Repositioning an orphan chemical library by inverse virtual screening.

PubMed

Giordano, Assunta; Forte, Giovanni; Massimo, Luigia; Riccio, Raffaele; Bifulco, Giuseppe; Di Micco, Simone

2018-04-12

Inverse Virtual Screening (IVS) is a docking based approach aimed to the evaluation of the virtual ability of a single compound to interact with a library of proteins. For the first time, we applied this methodology to a library of synthetic compounds, which proved to be inactive towards the target they were initially designed for. Trifluoromethyl-benzenesulfonamides 3-21 were repositioned by means of IVS identifying new lead compounds (14-16, 19 and 20) for the inhibition of erbB4 in the low micromolar range. Among these, compound 20 exhibited an interesting value of IC 50 on MCF7 cell lines, thus validating IVS in lead repurposing. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Statistical analysis of EGFR structures' performance in virtual screening

NASA Astrophysics Data System (ADS)

Li, Yan; Li, Xiang; Dong, Zigang

2015-11-01

In this work the ability of EGFR structures to distinguish true inhibitors from decoys in docking and MM-PBSA is assessed by statistical procedures. The docking performance depends critically on the receptor conformation and bound state. The enrichment of known inhibitors is well correlated with the difference between EGFR structures rather than the bound-ligand property. The optimal structures for virtual screening can be selected based purely on the complex information. And the mixed combination of distinct EGFR conformations is recommended for ensemble docking. In MM-PBSA, a variety of EGFR structures have identically good performance in the scoring and ranking of known inhibitors, indicating that the choice of the receptor structure has little effect on the screening.

New tools for sculpting cranial implants in a shared haptic augmented reality environment.

PubMed

Ai, Zhuming; Evenhouse, Ray; Leigh, Jason; Charbel, Fady; Rasmussen, Mary

2006-01-01

New volumetric tools were developed for the design and fabrication of high quality cranial implants from patient CT data. These virtual tools replace time consuming physical sculpting, mold making and casting steps. The implant is designed by medical professionals in tele-immersive collaboration. Virtual clay is added in the virtual defect area on the CT data using the adding tool. With force feedback the modeler can feel the edge of the defect and fill only the space where no bone is present. A carving tool and a smoothing tool are then used to sculpt and refine the implant. To make a physical evaluation, the skull with simulated defect and the implant are fabricated via stereolithography to allow neurosurgeons to evaluate the quality of the implant. Initial tests demonstrate a very high quality fit. These new haptic volumetric sculpting tools are a critical component of a comprehensive tele-immersive system.

Systematic Exploitation of Multiple Receptor Conformations for Virtual Ligand Screening

PubMed Central

Bottegoni, Giovanni; Rocchia, Walter; Rueda, Manuel; Abagyan, Ruben; Cavalli, Andrea

2011-01-01

The role of virtual ligand screening in modern drug discovery is to mine large chemical collections and to prioritize for experimental testing a comparatively small and diverse set of compounds with expected activity against a target. Several studies have pointed out that the performance of virtual ligand screening can be improved by taking into account receptor flexibility. Here, we systematically assess how multiple crystallographic receptor conformations, a powerful way of discretely representing protein plasticity, can be exploited in screening protocols to separate binders from non-binders. Our analyses encompass 36 targets of pharmaceutical relevance and are based on actual molecules with reported activity against those targets. The results suggest that an ensemble receptor-based protocol displays a stronger discriminating power between active and inactive molecules as compared to its standard single rigid receptor counterpart. Moreover, such a protocol can be engineered not only to enrich a higher number of active compounds, but also to enhance their chemical diversity. Finally, some clear indications can be gathered on how to select a subset of receptor conformations that is most likely to provide the best performance in a real life scenario. PMID:21625529

On various metrics used for validation of predictive QSAR models with applications in virtual screening and focused library design.

PubMed

Roy, Kunal; Mitra, Indrani

2011-07-01

Quantitative structure-activity relationships (QSARs) have important applications in drug discovery research, environmental fate modeling, property prediction, etc. Validation has been recognized as a very important step for QSAR model development. As one of the important objectives of QSAR modeling is to predict activity/property/toxicity of new chemicals falling within the domain of applicability of the developed models and QSARs are being used for regulatory decisions, checking reliability of the models and confidence of their predictions is a very important aspect, which can be judged during the validation process. One prime application of a statistically significant QSAR model is virtual screening for molecules with improved potency based on the pharmacophoric features and the descriptors appearing in the QSAR model. Validated QSAR models may also be utilized for design of focused libraries which may be subsequently screened for the selection of hits. The present review focuses on various metrics used for validation of predictive QSAR models together with an overview of the application of QSAR models in the fields of virtual screening and focused library design for diverse series of compounds with citation of some recent examples.

Large-scale systematic analysis of 2D fingerprint methods and parameters to improve virtual screening enrichments.

PubMed

Sastry, Madhavi; Lowrie, Jeffrey F; Dixon, Steven L; Sherman, Woody

2010-05-24

A systematic virtual screening study on 11 pharmaceutically relevant targets has been conducted to investigate the interrelation between 8 two-dimensional (2D) fingerprinting methods, 13 atom-typing schemes, 13 bit scaling rules, and 12 similarity metrics using the new cheminformatics package Canvas. In total, 157 872 virtual screens were performed to assess the ability of each combination of parameters to identify actives in a database screen. In general, fingerprint methods, such as MOLPRINT2D, Radial, and Dendritic that encode information about local environment beyond simple linear paths outperformed other fingerprint methods. Atom-typing schemes with more specific information, such as Daylight, Mol2, and Carhart were generally superior to more generic atom-typing schemes. Enrichment factors across all targets were improved considerably with the best settings, although no single set of parameters performed optimally on all targets. The size of the addressable bit space for the fingerprints was also explored, and it was found to have a substantial impact on enrichments. Small bit spaces, such as 1024, resulted in many collisions and in a significant degradation in enrichments compared to larger bit spaces that avoid collisions.

Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors

NASA Astrophysics Data System (ADS)

Kalid, Ori; Toledo Warshaviak, Dora; Shechter, Sharon; Sherman, Woody; Shacham, Sharon

2012-11-01

We present the Consensus Induced Fit Docking (cIFD) approach for adapting a protein binding site to accommodate multiple diverse ligands for virtual screening. This novel approach results in a single binding site structure that can bind diverse chemotypes and is thus highly useful for efficient structure-based virtual screening. We first describe the cIFD method and its validation on three targets that were previously shown to be challenging for docking programs (COX-2, estrogen receptor, and HIV reverse transcriptase). We then demonstrate the application of cIFD to the challenging discovery of irreversible Crm1 inhibitors. We report the identification of 33 novel Crm1 inhibitors, which resulted from the testing of 402 purchased compounds selected from a screening set containing 261,680 compounds. This corresponds to a hit rate of 8.2 %. The novel Crm1 inhibitors reveal diverse chemical structures, validating the utility of the cIFD method in a real-world drug discovery project. This approach offers a pragmatic way to implicitly account for protein flexibility without the additional computational costs of ensemble docking or including full protein flexibility during virtual screening.

A ranking method for the concurrent learning of compounds with various activity profiles.

PubMed

Dörr, Alexander; Rosenbaum, Lars; Zell, Andreas

2015-01-01

In this study, we present a SVM-based ranking algorithm for the concurrent learning of compounds with different activity profiles and their varying prioritization. To this end, a specific labeling of each compound was elaborated in order to infer virtual screening models against multiple targets. We compared the method with several state-of-the-art SVM classification techniques that are capable of inferring multi-target screening models on three chemical data sets (cytochrome P450s, dehydrogenases, and a trypsin-like protease data set) containing three different biological targets each. The experiments show that ranking-based algorithms show an increased performance for single- and multi-target virtual screening. Moreover, compounds that do not completely fulfill the desired activity profile are still ranked higher than decoys or compounds with an entirely undesired profile, compared to other multi-target SVM methods. SVM-based ranking methods constitute a valuable approach for virtual screening in multi-target drug design. The utilization of such methods is most helpful when dealing with compounds with various activity profiles and the finding of many ligands with an already perfectly matching activity profile is not to be expected.

Computational discovery of putative quorum sensing inhibitors against LasR and RhlR receptor proteins of Pseudomonas aeruginosa

NASA Astrophysics Data System (ADS)

Annapoorani, Angusamy; Umamageswaran, Venugopal; Parameswari, Radhakrishnan; Pandian, Shunmugiah Karutha; Ravi, Arumugam Veera

2012-09-01

Drugs have been discovered in the past mainly either by identification of active components from traditional remedies or by unpredicted discovery. A key motivation for the study of structure based virtual screening is the exploitation of such information to design targeted drugs. In this study, structure based virtual screening was used in search for putative quorum sensing inhibitors (QSI) of Pseudomonas aeruginosa. The virtual screening programme Glide version 5.5 was applied to screen 1,920 natural compounds/drugs against LasR and RhlR receptor proteins of P. aeruginosa. Based on the results of in silico docking analysis, five top ranking compounds namely rosmarinic acid, naringin, chlorogenic acid, morin and mangiferin were subjected to in vitro bioassays against laboratory strain PAO1 and two more antibiotic resistant clinical isolates, P. aeruginosa AS1 (GU447237) and P. aeruginosa AS2 (GU447238). Among the five compounds studied, except mangiferin other four compounds showed significant inhibition in the production of protease, elastase and hemolysin. Further, all the five compounds potentially inhibited the biofilm related behaviours. This interaction study provided promising ligands to inhibit the quorum sensing (QS) mediated virulence factors production in P. aeruginosa.

Vitual screening and binding mode elucidation of curcumin analogues on Cyclooxygenase-2 using AYO_COX2_V1.1 protocol

NASA Astrophysics Data System (ADS)

Mulatsari, E.; Mumpuni, E.; Herfian, A.

2017-05-01

Curcumin is yellow colored phenolic compounds contained in Curcuma longa. Curcumin is known to have biological activities as anti-inflammatory, antiviral, antioxidant, and anti-infective agent [1]. Synthesis of curcumin analogue compounds has been done and some of them had biological activity like curcumin. In this research, the virtual screening of curcumin analogue compounds has been conducted. The purpose of this research was to determine the activity of these compounds as selective Cyclooxygenase-2inhibitors in in-silico. Binding mode elucidation was made by active and inactive representative compounds to see the interaction of the amino acids in the binding site of the compounds. This research used AYO_COX2_V.1.1, a structure-based virtual screening protocol (SBVS) that has been validated by Mumpuni E et al, 2014 [2]. AYO_COX2_V.1.1 protocol using a variety of integrated applications such as SPORES, PLANTS, BKchem, OpenBabel and PyMOL. The results of virtual screening conducted on 49 curcumin analogue compounds obtained 8 compounds with 4 active amino acid residues (GLY340, ILE503, PHE343, and PHE367) that were considered active as COX-2 inhibitor.

The reliability and validity of measurements of human dental casts made by an intra-oral 3D scanner, with conventional hand-held digital callipers as the comparison measure.

PubMed

Rajshekar, Mithun; Julian, Roberta; Williams, Anne-Marie; Tennant, Marc; Forrest, Alex; Walsh, Laurence J; Wilson, Gary; Blizzard, Leigh

2017-09-01

Intra-oral 3D scanning of dentitions has the potential to provide a fast, accurate and non-invasive method of recording dental information. The aim of this study was to assess the reliability of measurements of human dental casts made using a portable intra-oral 3D scanner appropriate for field use. Two examiners each measured 84 tooth and 26 arch features of 50 sets of upper and lower human dental casts using digital hand-held callipers, and secondly using the measuring tool provided with the Zfx IntraScan intraoral 3D scanner applied to the virtual dental casts. The measurements were repeated at least one week later. Reliability and validity were quantified concurrently by calculation of intra-class correlation coefficients (ICC) and standard errors of measurement (SEM). The measurements of the 110 landmark features of human dental casts made using the intra-oral 3D scanner were virtually indistinguishable from measurements of the same features made using conventional hand-held callipers. The difference of means as a percentage of the average of the measurements by each method ranged between 0.030% and 1.134%. The intermethod SEMs ranged between 0.037% and 0.535%, and the inter-method ICCs ranged between 0.904 and 0.999, for both the upper and the lower arches. The inter-rater SEMs were one-half and the intra-method/rater SEMs were one-third of the inter-method values. This study demonstrates that the Zfx IntraScan intra-oral 3D scanner with its virtual on-screen measuring tool is a reliable and valid method for measuring the key features of dental casts. Copyright © 2017 Elsevier B.V. All rights reserved.

Using Hierarchical Virtual Screening To Combat Drug Resistance of the HIV-1 Protease.

PubMed

Li, Nan; Ainsworth, Richard I; Ding, Bo; Hou, Tingjun; Wang, Wei

2015-07-27

Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of highly active anti-retroviral therapy (HAART) that block the catalytic site of HIV protease, thus preventing maturation of the HIV virion. However, with two decades of PI prescriptions in clinical practice, drug-resistant HIV mutants have now been found for all of the PI drugs. Therefore, the continuous development of new PI drugs is crucial both to combat the existing drug-resistant HIV strains and to provide treatments for future patients. Here we purpose an HIV PI drug design strategy to select candidate PIs with binding energy distributions dominated by interactions with conserved protease residues in both wild-type and various drug-resistant mutants. On the basis of this strategy, we have constructed a virtual screening pipeline including combinatorial library construction, combinatorial docking, MM/GBSA-based rescoring, and reranking on the basis of the binding energy distribution. We have tested our strategy on lopinavir by modifying its two functional groups. From an initial 751 689 candidate molecules, 18 candidate inhibitors were selected using the pipeline for experimental validation. IC50 measurements and drug resistance predictions successfully identified two ligands with both HIV protease inhibitor activity and an improved drug resistance profile on 2382 HIV mutants. This study provides a proof of concept for the integration of MM/GBSA energy analysis and drug resistance information at the stage of virtual screening and sheds light on future HIV drug design and the use of virtual screening to combat drug resistance.

Virtual screening of integrase inhibitors by large scale binding free energy calculations: the SAMPL4 challenge

PubMed Central

Gallicchio, Emilio; Deng, Nanjie; He, Peng; Wickstrom, Lauren; Perryman, Alexander L.; Santiago, Daniel N.; Forli, Stefano; Olson, Arthur J.; Levy, Ronald M.

2014-01-01

As part of the SAMPL4 blind challenge, filtered AutoDock Vina ligand docking predictions and large scale binding energy distribution analysis method binding free energy calculations have been applied to the virtual screening of a focused library of candidate binders to the LEDGF site of the HIV integrase protein. The computational protocol leveraged docking and high level atomistic models to improve enrichment. The enrichment factor of our blind predictions ranked best among all of the computational submissions, and second best overall. This work represents to our knowledge the first example of the application of an all-atom physics-based binding free energy model to large scale virtual screening. A total of 285 parallel Hamiltonian replica exchange molecular dynamics absolute protein-ligand binding free energy simulations were conducted starting from docked poses. The setup of the simulations was fully automated, calculations were distributed on multiple computing resources and were completed in a 6-weeks period. The accuracy of the docked poses and the inclusion of intramolecular strain and entropic losses in the binding free energy estimates were the major factors behind the success of the method. Lack of sufficient time and computing resources to investigate additional protonation states of the ligands was a major cause of mispredictions. The experiment demonstrated the applicability of binding free energy modeling to improve hit rates in challenging virtual screening of focused ligand libraries during lead optimization. PMID:24504704

Electrophysiological characterization of 14-benzoyltalatisamine, a selective blocker of the delayed rectifier K+ channel found in virtual screening.

PubMed

Song, Ming-Ke; Liu, Hong; Jiang, Hua-Liang; Yue, Jian-Min; Hu, Guo-Yuan

2006-02-15

14-Benzoyltalatisamine is a potent and selective blocker of the delayed rectifier K+ channel found in a computational virtual screening study. The compound was found to block the K+ channel from the extracellular side. However, it is unclear whether 14-benzoyltalatisamine shares the same block mechanism with tetraethylammonium (TEA). In order to elucidate how the hit compound found by the virtual screening interacts with the outer vestibule of the K+ channel, the effects of 14-benzoyltalatisamine and TEA on the delayed rectifier K+ current of rat dissociated hippocampal neurons were compared using whole-cell voltage-clamp recording. External application of 14-benzoyltalatisamine and TEA reversibly inhibited the current with IC50 values of 10.1+/-2.2 microM and 1.05+/-0.21 mM, respectively. 14-Benzoyltalatisamine exerted voltage-dependent inhibition, markedly accelerated the decay of the current, and caused a significant hyperpolarizing shift of the steady-state activation curve, whereas TEA caused voltage-independent inhibition, without affecting the kinetic parameters of the current. The blockade by 14-benzoyltalatisamine, but not by TEA, was significantly diminished in a high K+ (60 mM) external solution. The potency of 14-benzoyltalatisamine was markedly reduced in the presence of 15 mM TEA. The results suggest that 14-benzoyltalatisamine bind to the external pore entry of the delayed rectifier K+ channel with partial insertion into the selectivity filter, which is in conformity with that predicted by the molecular docking model in the virtual screening.

Investigation of tracking systems properties in CAVE-type virtual reality systems

NASA Astrophysics Data System (ADS)

Szymaniak, Magda; Mazikowski, Adam; Meironke, Michał

2017-08-01

In recent years, many scientific and industrial centers in the world developed a virtual reality systems or laboratories. One of the most advanced solutions are Immersive 3D Visualization Lab (I3DVL), a CAVE-type (Cave Automatic Virtual Environment) laboratory. It contains two CAVE-type installations: six-screen installation arranged in a form of a cube, and four-screen installation, a simplified version of the previous one. The user feeling of "immersion" and interaction with virtual world depend on many factors, in particular on the accuracy of the tracking system of the user. In this paper properties of the tracking systems applied in I3DVL was investigated. For analysis two parameters were selected: the accuracy of the tracking system and the range of detection of markers by the tracking system in space of the CAVE. Measurements of system accuracy were performed for six-screen installation, equipped with four tracking cameras for three axes: X, Y, Z. Rotation around the Y axis was also analyzed. Measured tracking system shows good linear and rotating accuracy. The biggest issue was the range of the monitoring of markers inside the CAVE. It turned out, that the tracking system lose sight of the markers in the corners of the installation. For comparison, for a simplified version of CAVE (four-screen installation), equipped with eight tracking cameras, this problem was not occur. Obtained results will allow for improvement of cave quality.

Condorcet and borda count fusion method for ligand-based virtual screening.

PubMed

Ahmed, Ali; Saeed, Faisal; Salim, Naomie; Abdo, Ammar

2014-01-01

It is known that any individual similarity measure will not always give the best recall of active molecule structure for all types of activity classes. Recently, the effectiveness of ligand-based virtual screening approaches can be enhanced by using data fusion. Data fusion can be implemented using two different approaches: group fusion and similarity fusion. Similarity fusion involves searching using multiple similarity measures. The similarity scores, or ranking, for each similarity measure are combined to obtain the final ranking of the compounds in the database. The Condorcet fusion method was examined. This approach combines the outputs of similarity searches from eleven association and distance similarity coefficients, and then the winner measure for each class of molecules, based on Condorcet fusion, was chosen to be the best method of searching. The recall of retrieved active molecules at top 5% and significant test are used to evaluate our proposed method. The MDL drug data report (MDDR), maximum unbiased validation (MUV) and Directory of Useful Decoys (DUD) data sets were used for experiments and were represented by 2D fingerprints. Simulated virtual screening experiments with the standard two data sets show that the use of Condorcet fusion provides a very simple way of improving the ligand-based virtual screening, especially when the active molecules being sought have a lowest degree of structural heterogeneity. However, the effectiveness of the Condorcet fusion was increased slightly when structural sets of high diversity activities were being sought.

Condorcet and borda count fusion method for ligand-based virtual screening

PubMed Central

2014-01-01

Background It is known that any individual similarity measure will not always give the best recall of active molecule structure for all types of activity classes. Recently, the effectiveness of ligand-based virtual screening approaches can be enhanced by using data fusion. Data fusion can be implemented using two different approaches: group fusion and similarity fusion. Similarity fusion involves searching using multiple similarity measures. The similarity scores, or ranking, for each similarity measure are combined to obtain the final ranking of the compounds in the database. Results The Condorcet fusion method was examined. This approach combines the outputs of similarity searches from eleven association and distance similarity coefficients, and then the winner measure for each class of molecules, based on Condorcet fusion, was chosen to be the best method of searching. The recall of retrieved active molecules at top 5% and significant test are used to evaluate our proposed method. The MDL drug data report (MDDR), maximum unbiased validation (MUV) and Directory of Useful Decoys (DUD) data sets were used for experiments and were represented by 2D fingerprints. Conclusions Simulated virtual screening experiments with the standard two data sets show that the use of Condorcet fusion provides a very simple way of improving the ligand-based virtual screening, especially when the active molecules being sought have a lowest degree of structural heterogeneity. However, the effectiveness of the Condorcet fusion was increased slightly when structural sets of high diversity activities were being sought. PMID:24883114

iVirtualWorld: A Domain-Oriented End-User Development Environment for Building 3D Virtual Chemistry Experiments

ERIC Educational Resources Information Center

Zhong, Ying

2013-01-01

Virtual worlds are well-suited for building virtual laboratories for educational purposes to complement hands-on physical laboratories. However, educators may face technical challenges because developing virtual worlds requires skills in programming and 3D design. Current virtual world building tools are developed for users who have programming…

Design for learning: deconstructing virtual patient activities.

PubMed

Ellaway, Rachel H; Davies, David

2011-01-01

Digital technologies are used in almost every aspect of contemporary health professional education (HPE) but our understanding of their true potential as instructional tools rather than administrative tools has not significantly advanced in the last decade. One notable exception to this has been the rise of the 'virtual patient' as an educational intervention in HPE. This article attempts to deconstruct the virtual patient concept by developing a model of virtual patients as artifacts with intrinsic encoded properties and emergent constructed properties that build on the core concept of 'activity'.

Novel Mycosin Protease MycP1 Inhibitors Identified by Virtual Screening and 4D Fingerprints

PubMed Central

2015-01-01

The rise of drug-resistant Mycobacterium tuberculosis lends urgency to the need for new drugs for the treatment of tuberculosis (TB). The identification of a serine protease, mycosin protease-1 (MycP1), as the crucial agent in hydrolyzing the virulence factor, ESX-secretion-associated protein B (EspB), potentially opens the door to new tuberculosis treatment options. Using the crystal structure of mycobacterial MycP1 in the apo form, we performed an iterative ligand- and structure-based virtual screening (VS) strategy to identify novel, nonpeptide, small-molecule inhibitors against MycP1 protease. Screening of ∼485 000 ligands from databases at the Genomics Research Institute (GRI) at the University of Cincinnati and the National Cancer Institute (NCI) using our VS approach, which integrated a pharmacophore model and consensus molecular shape patterns of active ligands (4D fingerprints), identified 81 putative inhibitors, and in vitro testing subsequently confirmed two of them as active inhibitors. Thereafter, the lead structures of each VS round were used to generate a new 4D fingerprint that enabled virtual rescreening of the chemical libraries. Finally, the iterative process identified a number of diverse scaffolds as lead compounds that were tested and found to have micromolar IC50 values against the MycP1 target. This study validated the efficiency of the SABRE 4D fingerprints as a means of identifying novel lead compounds in each screening round of the databases. Together, these results underscored the value of using a combination of in silico iterative ligand- and structure-based virtual screening of chemical libraries with experimental validation for the identification of promising structural scaffolds, such as the MycP1 inhibitors. PMID:24628123

Anticonvulsant activity of artificial sweeteners: a structural link between sweet-taste receptor T1R3 and brain glutamate receptors.

PubMed

Talevi, Alan; Enrique, Andrea V; Bruno-Blanch, Luis E

2012-06-15

A virtual screening campaign based on application of a topological discriminant function capable of identifying novel anticonvulsant agents indicated several widely-used artificial sweeteners as potential anticonvulsant candidates. Acesulfame potassium, cyclamate and saccharin were tested in the Maximal Electroshock Seizure model (mice, ip), showing moderate anticonvulsant activity. We hypothesized a probable structural link between the receptor responsible of sweet taste and anticonvulsant molecular targets. Bioinformatic tools confirmed a highly significant sequence-similarity between taste-related protein T1R3 and several metabotropic glutamate receptors from different species, including glutamate receptors upregulated in epileptogenesis and certain types of epilepsy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Computational Modeling and Simulation of Developmental ...

EPA Pesticide Factsheets

SYNOPSIS: The question of how tissues and organs are shaped during development is crucial for understanding human birth defects. Data from high-throughput screening assays on human stem cells may be utilized predict developmental toxicity with reasonable accuracy. Other types of models are necessary, however, for mechanism-specific analysis because embryogenesis requires precise timing and control. Agent-based modeling and simulation (ABMS) is an approach to virtually reconstruct these dynamics, cell-by-cell and interaction-by-interaction. Using ABMS, HTS lesions from ToxCast can be integrated with patterning systems heuristically to propagate key events This presentation to FDA-CFSAN will update progress on the applications of in silico modeling tools and approaches for assessing developmental toxicity.

[What do virtual reality tools bring to child and adolescent psychiatry?

PubMed

Bioulac, S; de Sevin, E; Sagaspe, P; Claret, A; Philip, P; Micoulaud-Franchi, J A; Bouvard, M P

2018-06-01

Virtual reality is a relatively new technology that enables individuals to immerse themselves in a virtual world. It offers several advantages including a more realistic, lifelike environment that may allow subjects to "forget" they are being assessed, allow a better participation and an increased generalization of learning. Moreover, the virtual reality system can provide multimodal stimuli, such as visual and auditory stimuli, and can also be used to evaluate the patient's multimodal integration and to aid rehabilitation of cognitive abilities. The use of virtual reality to treat various psychiatric disorders in adults (phobic anxiety disorders, post-traumatic stress disorder, eating disorders, addictions…) and its efficacy is supported by numerous studies. Similar research for children and adolescents is lagging behind. This may be particularly beneficial to children who often show great interest and considerable success on computer, console or videogame tasks. This article will expose the main studies that have used virtual reality with children and adolescents suffering from psychiatric disorders. The use of virtual reality to treat anxiety disorders in adults is gaining popularity and its efficacy is supported by various studies. Most of the studies attest to the significant efficacy of the virtual reality exposure therapy (or in virtuo exposure). In children, studies have covered arachnophobia social anxiety and school refusal phobia. Despite the limited number of studies, results are very encouraging for treatment in anxiety disorders. Several studies have reported the clinical use of virtual reality technology for children and adolescents with autistic spectrum disorders (ASD). Extensive research has proven the efficiency of technologies as support tools for therapy. Researches are found to be focused on communication and on learning and social imitation skills. Virtual reality is also well accepted by subjects with ASD. The virtual environment offers the opportunity to administer controlled tasks such as the typical neuropsychological tools, but in an environment much more like a standard classroom. The virtual reality classroom offers several advantages compared to classical tools such as more realistic and lifelike environment but also records various measures in standardized conditions. Most of the studies using a virtual classroom have found that children with Attention Deficit/Hyperactivity Disorder make significantly fewer correct hits and more commission errors compared with controls. The virtual classroom has proven to be a good clinical tool for evaluation of attention in ADHD. For eating disorders, cognitive behavioural therapy (CBT) program enhanced by a body image specific component using virtual reality techniques was shown to be more efficient than cognitive behavioural therapy alone. The body image-specific component using virtual reality techniques boots efficiency and accelerates the CBT change process for eating disorders. Virtual reality is a relatively new technology and its application in child and adolescent psychiatry is recent. However, this technique is still in its infancy and much work is needed including controlled trials before it can be introduced in routine clinical use. Virtual reality interventions should also investigate how newly acquired skills are transferred to the real world. At present virtual reality can be considered a useful tool in evaluation and treatment for child and adolescent disorders. Copyright © 2017 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Virtual environment architecture for rapid application development

NASA Technical Reports Server (NTRS)

Grinstein, Georges G.; Southard, David A.; Lee, J. P.

1993-01-01

We describe the MITRE Virtual Environment Architecture (VEA), a product of nearly two years of investigations and prototypes of virtual environment technology. This paper discusses the requirements for rapid prototyping, and an architecture we are developing to support virtual environment construction. VEA supports rapid application development by providing a variety of pre-built modules that can be reconfigured for each application session. The modules supply interfaces for several types of interactive I/O devices, in addition to large-screen or head-mounted displays.

Calculating an optimal box size for ligand docking and virtual screening against experimental and predicted binding pockets.

PubMed

Feinstein, Wei P; Brylinski, Michal

2015-01-01

Computational approaches have emerged as an instrumental methodology in modern research. For example, virtual screening by molecular docking is routinely used in computer-aided drug discovery. One of the critical parameters for ligand docking is the size of a search space used to identify low-energy binding poses of drug candidates. Currently available docking packages often come with a default protocol for calculating the box size, however, many of these procedures have not been systematically evaluated. In this study, we investigate how the docking accuracy of AutoDock Vina is affected by the selection of a search space. We propose a new procedure for calculating the optimal docking box size that maximizes the accuracy of binding pose prediction against a non-redundant and representative dataset of 3,659 protein-ligand complexes selected from the Protein Data Bank. Subsequently, we use the Directory of Useful Decoys, Enhanced to demonstrate that the optimized docking box size also yields an improved ranking in virtual screening. Binding pockets in both datasets are derived from the experimental complex structures and, additionally, predicted by eFindSite. A systematic analysis of ligand binding poses generated by AutoDock Vina shows that the highest accuracy is achieved when the dimensions of the search space are 2.9 times larger than the radius of gyration of a docking compound. Subsequent virtual screening benchmarks demonstrate that this optimized docking box size also improves compound ranking. For instance, using predicted ligand binding sites, the average enrichment factor calculated for the top 1 % (10 %) of the screening library is 8.20 (3.28) for the optimized protocol, compared to 7.67 (3.19) for the default procedure. Depending on the evaluation metric, the optimal docking box size gives better ranking in virtual screening for about two-thirds of target proteins. This fully automated procedure can be used to optimize docking protocols in order to improve the ranking accuracy in production virtual screening simulations. Importantly, the optimized search space systematically yields better results than the default method not only for experimental pockets, but also for those predicted from protein structures. A script for calculating the optimal docking box size is freely available at www.brylinski.org/content/docking-box-size. Graphical AbstractWe developed a procedure to optimize the box size in molecular docking calculations. Left panel shows the predicted binding pose of NADP (green sticks) compared to the experimental complex structure of human aldose reductase (blue sticks) using a default protocol. Right panel shows the docking accuracy using an optimized box size.

Benchmark of four popular virtual screening programs: construction of the active/decoy dataset remains a major determinant of measured performance.

PubMed

Chaput, Ludovic; Martinez-Sanz, Juan; Saettel, Nicolas; Mouawad, Liliane

2016-01-01

In a structure-based virtual screening, the choice of the docking program is essential for the success of a hit identification. Benchmarks are meant to help in guiding this choice, especially when undertaken on a large variety of protein targets. Here, the performance of four popular virtual screening programs, Gold, Glide, Surflex and FlexX, is compared using the Directory of Useful Decoys-Enhanced database (DUD-E), which includes 102 targets with an average of 224 ligands per target and 50 decoys per ligand, generated to avoid biases in the benchmarking. Then, a relationship between these program performances and the properties of the targets or the small molecules was investigated. The comparison was based on two metrics, with three different parameters each. The BEDROC scores with α = 80.5, indicated that, on the overall database, Glide succeeded (score > 0.5) for 30 targets, Gold for 27, FlexX for 14 and Surflex for 11. The performance did not depend on the hydrophobicity nor the openness of the protein cavities, neither on the families to which the proteins belong. However, despite the care in the construction of the DUD-E database, the small differences that remain between the actives and the decoys likely explain the successes of Gold, Surflex and FlexX. Moreover, the similarity between the actives of a target and its crystal structure ligand seems to be at the basis of the good performance of Glide. When all targets with significant biases are removed from the benchmarking, a subset of 47 targets remains, for which Glide succeeded for only 5 targets, Gold for 4 and FlexX and Surflex for 2. The performance dramatic drop of all four programs when the biases are removed shows that we should beware of virtual screening benchmarks, because good performances may be due to wrong reasons. Therefore, benchmarking would hardly provide guidelines for virtual screening experiments, despite the tendency that is maintained, i.e., Glide and Gold display better performance than FlexX and Surflex. We recommend to always use several programs and combine their results. Graphical AbstractSummary of the results obtained by virtual screening with the four programs, Glide, Gold, Surflex and FlexX, on the 102 targets of the DUD-E database. The percentage of targets with successful results, i.e., with BDEROC(α = 80.5) > 0.5, when the entire database is considered are in Blue, and when targets with biased chemical libraries are removed are in Red.

Multi-modal virtual environment research at Armstrong Laboratory

NASA Technical Reports Server (NTRS)

Eggleston, Robert G.

1995-01-01

One mission of the Paul M. Fitts Human Engineering Division of Armstrong Laboratory is to improve the user interface for complex systems through user-centered exploratory development and research activities. In support of this goal, many current projects attempt to advance and exploit user-interface concepts made possible by virtual reality (VR) technologies. Virtual environments may be used as a general purpose interface medium, an alternative display/control method, a data visualization and analysis tool, or a graphically based performance assessment tool. An overview is given of research projects within the division on prototype interface hardware/software development, integrated interface concept development, interface design and evaluation tool development, and user and mission performance evaluation tool development.

minimega

DOE Office of Scientific and Technical Information (OSTI.GOV)

David Fritz, John Floren

2013-08-27

Minimega is a simple emulytics platform for creating testbeds of networked devices. The platform consists of easily deployable tools to facilitate bringing up large networks of virtual machines including Windows, Linux, and Android. Minimega attempts to allow experiments to be brought up quickly with nearly no configuration. Minimega also includes tools for simple cluster management, as well as tools for creating Linux based virtual machine images.

Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation

PubMed Central

Szelag, Malgorzata; Czerwoniec, Anna; Wesoly, Joanna; Bluyssen, Hans A. R.

2015-01-01

Signal transducers and activators of transcription (STATs) facilitate action of cytokines, growth factors and pathogens. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The active dimers induce gene transcription in the nucleus by binding to a specific DNA-response element in the promoter of target genes. Abnormal activation of STAT signaling pathways is implicated in many human diseases, like cancer, inflammation and auto-immunity. Searches for STAT-targeting compounds, exploring the phosphotyrosine (pTyr)-SH2 interaction site, yielded many small molecules for STAT3 but sparsely for other STATs. However, many of these inhibitors seem not STAT3-specific, thereby questioning the present modeling and selection strategies of SH2 domain-based STAT inhibitors. We generated new 3D structure models for all human (h)STATs and developed a comparative in silico docking strategy to obtain further insight into STAT-SH2 cross-binding specificity of a selection of previously identified STAT3 inhibitors. Indeed, by primarily targeting the highly conserved pTyr-SH2 binding pocket the majority of these compounds exhibited similar binding affinity and tendency scores for all STATs. By comparative screening of a natural product library we provided initial proof for the possibility to identify STAT1 as well as STAT3-specific inhibitors, introducing the ‘STAT-comparative binding affinity value’ and ‘ligand binding pose variation’ as selection criteria. In silico screening of a multi-million clean leads (CL) compound library for binding of all STATs, likewise identified potential specific inhibitors for STAT1 and STAT3 after docking validation. Based on comparative virtual screening and docking validation, we developed a novel STAT inhibitor screening tool that allows identification of specific STAT1 and STAT3 inhibitory compounds. This could increase our understanding of the functional role of these STATs in different diseases and benefit the clinical need for more drugable STAT inhibitors with high specificity, potency and excellent bioavailability. PMID:25710482

Not Just a Game … When We Play Together, We Learn Together: Interactive Virtual Environments and Gaming Engines for Geospatial Visualization

NASA Astrophysics Data System (ADS)

Shipman, J. S.; Anderson, J. W.

2017-12-01

An ideal tool for ecologists and land managers to investigate the impacts of both projected environmental changes and policy alternatives is the creation of immersive, interactive, virtual landscapes. As a new frontier in visualizing and understanding geospatial data, virtual landscapes require a new toolbox for data visualization that includes traditional GIS tools and uncommon tools such as the Unity3d game engine. Game engines provide capabilities to not only explore data but to build and interact with dynamic models collaboratively. These virtual worlds can be used to display and illustrate data that is often more understandable and plausible to both stakeholders and policy makers than is achieved using traditional maps.Within this context we will present funded research that has been developed utilizing virtual landscapes for geographic visualization and decision support among varied stakeholders. We will highlight the challenges and lessons learned when developing interactive virtual environments that require large multidisciplinary team efforts with varied competences. The results will emphasize the importance of visualization and interactive virtual environments and the link with emerging research disciplines within Visual Analytics.

[The inter-university learning website: a national university network for online teaching of pathology].

PubMed

Gauchotte, Guillaume; Ameisen, David; Boutonnat, Jean; Battistella, Maxime; Copie, Christiane; Garcia, Stéphane; Rigau, Valérie; Galateau-Sallé, Françoise; Terris, Benoit; Vergier, Béatrice; Wendum, Dominique; Bertheau, Philippe

2013-06-01

Building online teaching materials is a highly time and energy consuming task for teachers of a single university. With the help of the Collège des pathologistes, we initiated a French national university network for building mutualized online teaching pathology cases, tests and other pedagogic resources. Nineteen French universities are associated to this project, initially funded by UNF3S (http://www.unf3s.org/). One national e-learning Moodle platform (http://virtual-slides.univ-paris7.fr/moodle/) contains texts, medias and URL pointing toward decentralized virtual slides. The Moodle interface has been explained to the teachers since september 2011 using web-based conferences with screen-sharing. The following contents have been created: 20 clinical cases, several tests with multiple choices and short answer questions, and gross examination videos. A survey with 16 teachers and students showed a 94 % satisfaction rate, most of the 16 participants being favorable to the development of e-learning, in parallel with other courses in classroom. These tools will be further developed for the different study levels of pathology. In conclusion, these tools offer very interesting perspectives for pathology teaching. The organization of a national inter-university network is a useful way to create and share numerous and good-quality pedagogic resources. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Dynamic undocking and the quasi-bound state as tools for drug discovery

NASA Astrophysics Data System (ADS)

Ruiz-Carmona, Sergio; Schmidtke, Peter; Luque, F. Javier; Baker, Lisa; Matassova, Natalia; Davis, Ben; Roughley, Stephen; Murray, James; Hubbard, Rod; Barril, Xavier

2017-03-01

There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein-ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important native contact with the receptor. This non-equilibrium property is surprisingly effective in virtual screening because true ligands form more-resilient interactions than decoys. Notably, DUck is orthogonal to docking and other 'thermodynamic' methods. We demonstrate the potential of the docking-undocking combination in a fragment screening against the molecular chaperone and oncology target Hsp90, for which we obtain novel chemotypes and a hit rate that approaches 40%.

Magnetic resonance imaging of granular materials

NASA Astrophysics Data System (ADS)

Stannarius, Ralf

2017-05-01

Magnetic Resonance Imaging (MRI) has become one of the most important tools to screen humans in medicine; virtually every modern hospital is equipped with a Nuclear Magnetic Resonance (NMR) tomograph. The potential of NMR in 3D imaging tasks is by far greater, but there is only "a handful" of MRI studies of particulate matter. The method is expensive, time-consuming, and requires a deep understanding of pulse sequences, signal acquisition, and processing. We give a short introduction into the physical principles of this imaging technique, describe its advantages and limitations for the screening of granular matter, and present a number of examples of different application purposes, from the exploration of granular packing, via the detection of flow and particle diffusion, to real dynamic measurements. Probably, X-ray computed tomography is preferable in most applications, but fast imaging of single slices with modern MRI techniques is unmatched, and the additional opportunity to retrieve spatially resolved flow and diffusion profiles without particle tracking is a unique feature.

Contributions of computational chemistry and biophysical techniques to fragment-based drug discovery.

PubMed

Gozalbes, Rafael; Carbajo, Rodrigo J; Pineda-Lucena, Antonio

2010-01-01

In the last decade, fragment-based drug discovery (FBDD) has evolved from a novel approach in the search of new hits to a valuable alternative to the high-throughput screening (HTS) campaigns of many pharmaceutical companies. The increasing relevance of FBDD in the drug discovery universe has been concomitant with an implementation of the biophysical techniques used for the detection of weak inhibitors, e.g. NMR, X-ray crystallography or surface plasmon resonance (SPR). At the same time, computational approaches have also been progressively incorporated into the FBDD process and nowadays several computational tools are available. These stretch from the filtering of huge chemical databases in order to build fragment-focused libraries comprising compounds with adequate physicochemical properties, to more evolved models based on different in silico methods such as docking, pharmacophore modelling, QSAR and virtual screening. In this paper we will review the parallel evolution and complementarities of biophysical techniques and computational methods, providing some representative examples of drug discovery success stories by using FBDD.

Imaging screening of catastrophic neurological events using a software tool: preliminary results.

PubMed

Fernandes, A P; Gomes, A; Veiga, J; Ermida, D; Vardasca, T

2015-05-01

In Portugal, as in most countries, the most frequent organ donors are brain-dead donors. To answer the increasing need for transplants, donation programs have been implemented. The goal is to recognize virtually all the possible and potential brain-dead donors admitted to hospitals. The aim of this work was to describe preliminary results of a software application designed to identify devastating neurological injury victims who may progress to brain death and can be possible organ donors. This was an observational, longitudinal study with retrospective data collection. The software application is an automatic algorithm based on natural language processing for selected keywords/expressions present in the cranio-encephalic computerized tomography (CE CT) scan reports to identify catastrophic neurological situations, with e-mail notification to the Transplant Coordinator (TC). The first 7 months of this application were analyzed and compared with the standard clinical evaluation methodology. The imaging identification tool showed a sensitivity of 77% and a specificity of 66%; predictive positive value (PPV) was 0.8 and predictive negative value (PNV) was 0.7 for the identification of catastrophic neurological events. The methodology proposed in this work seems promising in improving the screening efficiency of critical neurological events. Copyright © 2015 Elsevier Inc. All rights reserved.

Applications of computer-aided approaches in the development of hepatitis C antiviral agents.

PubMed

Ganesan, Aravindhan; Barakat, Khaled

2017-04-01

Hepatitis C virus (HCV) is a global health problem that causes several chronic life-threatening liver diseases. The numbers of people affected by HCV are rising annually. Since 2011, the FDA has approved several anti-HCV drugs; while many other promising HCV drugs are currently in late clinical trials. Areas covered: This review discusses the applications of different computational approaches in HCV drug design. Expert opinion: Molecular docking and virtual screening approaches have emerged as a low-cost tool to screen large databases and identify potential small-molecule hits against HCV targets. Ligand-based approaches are useful for filtering-out compounds with rich physicochemical properties to inhibit HCV targets. Molecular dynamics (MD) remains a useful tool in optimizing the ligand-protein complexes and understand the ligand binding modes and drug resistance mechanisms in HCV. Despite their varied roles, the application of in-silico approaches in HCV drug design is still in its infancy. A more mature application should aim at modelling the whole HCV replicon in its active form and help to identify new effective druggable sites within the replicon system. With more technological advancements, the roles of computer-aided methods are only going to increase several folds in the development of next-generation HCV drugs.

DigBody®: A new 3D modeling tool for nasal virtual surgery.

PubMed

Burgos, M A; Sanmiguel-Rojas, E; Singh, Narinder; Esteban-Ortega, F

2018-07-01

Recent studies have demonstrated that a significant number of surgical procedures for nasal airway obstruction (NAO) have a high rate of surgical failure. In part, this problem is due to the lack of reliable objective clinical parameters to aid surgeons during preoperative planning. Modeling tools that allow virtual surgery to be performed do exist, but all require direct manipulation of computed tomography (CT) or magnetic resonance imaging (MRI) data. Specialists in Rhinology have criticized these tools for their complex user interface, and have requested more intuitive, user-friendly and powerful software to make virtual surgery more accessible and realistic. In this paper we present a new virtual surgery software tool, DigBody ® . This new surgery module is integrated into the computational fluid dynamics (CFD) program MeComLand ® , which was developed exclusively to analyze nasal airflow. DigBody ® works directly with a 3D nasal model that mimics real surgery. Furthermore, this surgery module permits direct assessment of the operated cavity following virtual surgery by CFD simulation. The effectiveness of DigBody ® has been demonstrated by real surgery on two patients based on prior virtual operation results. Both subjects experienced excellent surgical outcomes with no residual nasal obstruction. This tool has great potential to aid surgeons in modeling potential surgical maneuvers, minimizing complications, and being confident that patients will receive optimal postoperative outcomes, validated by personalized CFD testing. Copyright © 2018 Elsevier Ltd. All rights reserved.

The European Virtual Observatory EURO-VO | Euro-VO

Science.gov Websites

: VOTECH EuroVO-DCA EuroVO-AIDA EuroVO-ICE The European Virtual Observatory EURO-VO The Virtual Observatory news Workshop on Virtual Observatory Tools and their Applications, Krakow, Poland June 16-18, organized present the Astronomical Virtual Observatory at the Copernicus (European Earth Observation Programme) Big

Modeling of luminance distribution in CAVE-type virtual reality systems

NASA Astrophysics Data System (ADS)

Meironke, Michał; Mazikowski, Adam

2017-08-01

At present, one of the most advanced virtual reality systems are CAVE-type (Cave Automatic Virtual Environment) installations. Such systems are usually consisted of four, five or six projection screens and in case of six screens arranged in form of a cube. Providing the user with a high level of immersion feeling in such systems is largely dependent of optical properties of the system. The modeling of physical phenomena plays nowadays a huge role in the most fields of science and technology. It allows to simulate work of device without a need to make any changes in the physical constructions. In this paper distribution of luminance in CAVE-type virtual reality systems were modelled. Calculations were performed for the model of 6-walled CAVE-type installation, based on Immersive 3D Visualization Laboratory, situated at the Faculty of Electronics, Telecommunications and Informatics at the Gdańsk University of Technology. Tests have been carried out for two different scattering distribution of the screen material in order to check how these characteristicinfluence on the luminance distribution of the whole CAVE. The basis assumption and simplification of modeled CAVE-type installation and results were presented. The brief discussion about the results and usefulness of developed model were also carried out.

Virtual screening for potential inhibitors of bacterial MurC and MurD ligases.

PubMed

Tomašić, Tihomir; Kovač, Andreja; Klebe, Gerhard; Blanot, Didier; Gobec, Stanislav; Kikelj, Danijel; Mašič, Lucija Peterlin

2012-03-01

Mur ligases are bacterial enzymes involved in the cytoplasmic steps of peptidoglycan biosynthesis and are viable targets for antibacterial drug discovery. We have performed virtual screening for potential ATP-competitive inhibitors targeting MurC and MurD ligases, using a protocol of consecutive hierarchical filters. Selected compounds were evaluated for inhibition of MurC and MurD ligases, and weak inhibitors possessing dual inhibitory activity have been identified. These compounds represent new scaffolds for further optimisation towards multiple Mur ligase inhibitors with improved inhibitory potency.

Rapid identification of Keap1-Nrf2 small-molecule inhibitors through structure-based virtual screening and hit-based substructure search.

PubMed

Zhuang, Chunlin; Narayanapillai, Sreekanth; Zhang, Wannian; Sham, Yuk Yin; Xing, Chengguo

2014-02-13

In this study, rapid structure-based virtual screening and hit-based substructure search were utilized to identify small molecules that disrupt the interaction of Keap1-Nrf2. Special emphasis was placed toward maximizing the exploration of chemical diversity of the initial hits while economically establishing informative structure-activity relationship (SAR) of novel scaffolds. Our most potent noncovalent inhibitor exhibits three times improved cellular activation in Nrf2 activation than the most active noncovalent Keap1 inhibitor known to date.

Virtual Environment Computer Simulations to Support Human Factors Engineering and Operations Analysis for the RLV Program

NASA Technical Reports Server (NTRS)

Lunsford, Myrtis Leigh

1998-01-01

The Army-NASA Virtual Innovations Laboratory (ANVIL) was recently created to provide virtual reality tools for performing Human Engineering and operations analysis for both NASA and the Army. The author's summer research project consisted of developing and refining these tools for NASA's Reusable Launch Vehicle (RLV) program. Several general simulations were developed for use by the ANVIL for the evaluation of the X34 Engine Changeout procedure. These simulations were developed with the software tool dVISE 4.0.0 produced by Division Inc. All software was run on an SGI Indigo2 High Impact. This paper describes the simulations, various problems encountered with the simulations, other summer activities, and possible work for the future. We first begin with a brief description of virtual reality systems.

Providing Guidance in Virtual Lab Experimentation: The Case of an Experiment Design Tool

ERIC Educational Resources Information Center

Efstathiou, Charalampos; Hovardas, Tasos; Xenofontos, Nikoletta A.; Zacharia, Zacharias C.; deJong, Ton; Anjewierden, Anjo; van Riesen, Siswa A. N.

2018-01-01

The present study employed a quasi-experimental design to assess a computer-based tool, which was intended to scaffold the task of designing experiments when using a virtual lab for the process of experimentation. In particular, we assessed the impact of this tool on primary school students' cognitive processes and inquiry skills before and after…

Virtual Beach Manager Toolset

EPA Science Inventory

The Virtual Beach Manager Toolset (VB) is a set of decision support software tools developed to help local beach managers make decisions as to when beaches should be closed due to predicted high levels of water borne pathogens. The tools are being developed under the umbrella of...

Virtual screening of Indonesian flavonoid as neuraminidase inhibitor of influenza a subtype H5N1

NASA Astrophysics Data System (ADS)

Parikesit, A. A.; Ardiansah, B.; Handayani, D. M.; Tambunan, U. S. F.; Kerami, D.

2016-02-01

Highly Pathogenic Avian Influenza (HPAI) H5N1 poses a significant threat to animal and human health worldwide. The number of H5N1 infection in Indonesia is the highest during 2005-2013, with a mortality rate up to 83%. A mutation that occurred in H5N1 strain made it resistant to commercial antiviral agents such as oseltamivir and zanamivir, so the more potent antiviral agent is needed. In this study, virtual screening of Indonesian flavonoid as neuraminidase inhibitor of H5N1 was conducted. Total 491 flavonoid compound obtained from HerbalDB were screened. Molecular docking was performed using MOE 2008.10. This research resulted in Guajavin B as the best ligand.

Computer-aided discovery in antimicrobial research: In silico model for virtual screening of potent and safe anti-pseudomonas agents.

PubMed

Speck-Planche, Alejandro; Cordeiro, Maria N D S

2015-01-01

Resistance of bacteria to current antibiotics is an alarming health problem. In this sense, Pseudomonas represents a genus of Gram-negative pathogens, which has emerged as one of the most dangerous species causing nosocomial infections. Despite the effort of the scientific community, drug resistant strains of bacteria belonging to Pseudomonas spp. prevail. The high costs associated to drug discovery and the urgent need for more efficient antimicrobial chemotherapies envisage the fact that computeraided methods can rationalize several stages involved in the development of a new drug. In this work, we introduce a chemoinformatic methodology devoted to the construction of a multitasking model for quantitative-structure biological effect relationships (mtk-QSBER). The purpose of this model was to perform simultaneous predictions of anti-Pseudomonas activities and ADMET (absorption, distribution, metabolism, elimination, and toxicity) properties of organic compounds. The mtk-QSBER model was created from a large and heterogeneous dataset (more than 54000 cases) and displayed accuracies higher than 90% in both training and prediction sets. In order to demonstrate the applicability of our mtk-QSBER model, we used the investigational antibacterial drug delafloxacin as a case of study, for which experimental results were recently reported. The predictions performed for many biological effects of this drug exhibited a remarkable convergence with the experimental assays, confirming that our model can serve as useful tool for virtual screening of potent and safer anti-Pseudomonas agents.

DockoMatic 2.0: high throughput inverse virtual screening and homology modeling.

PubMed

Bullock, Casey; Cornia, Nic; Jacob, Reed; Remm, Andrew; Peavey, Thomas; Weekes, Ken; Mallory, Chris; Oxford, Julia T; McDougal, Owen M; Andersen, Timothy L

2013-08-26

DockoMatic is a free and open source application that unifies a suite of software programs within a user-friendly graphical user interface (GUI) to facilitate molecular docking experiments. Here we describe the release of DockoMatic 2.0; significant software advances include the ability to (1) conduct high throughput inverse virtual screening (IVS); (2) construct 3D homology models; and (3) customize the user interface. Users can now efficiently setup, start, and manage IVS experiments through the DockoMatic GUI by specifying receptor(s), ligand(s), grid parameter file(s), and docking engine (either AutoDock or AutoDock Vina). DockoMatic automatically generates the needed experiment input files and output directories and allows the user to manage and monitor job progress. Upon job completion, a summary of results is generated by Dockomatic to facilitate interpretation by the user. DockoMatic functionality has also been expanded to facilitate the construction of 3D protein homology models using the Timely Integrated Modeler (TIM) wizard. The wizard TIM provides an interface that accesses the basic local alignment search tool (BLAST) and MODELER programs and guides the user through the necessary steps to easily and efficiently create 3D homology models for biomacromolecular structures. The DockoMatic GUI can be customized by the user, and the software design makes it relatively easy to integrate additional docking engines, scoring functions, or third party programs. DockoMatic is a free comprehensive molecular docking software program for all levels of scientists in both research and education.

An Ultra-Precise Method for the Nano Thin-Film Removal

NASA Astrophysics Data System (ADS)

Pa, P. S.

In this research an electrode-set is used to investigate via an ultra-precise method for the removal of Indium Tin Oxide (ITO) thin-film microstructure from defective display panels to conquer the low yield rate in display panel production as to from imperfect Indium Tin Oxide layer deposition is well known. This process, which involves the removal of ITO layer substructure by means of an electrochemical removal (ECMR), is of major interest to the optoelectronics semiconductor industry. In this electro machining process a high current flow and high feed rate of the display (color filter) achieves complete and efficient removal of the ITO layer. The ITO thin-film can be removed completely by a proper combination of feed rate and electric power. A small gap between the diameter cathode virtual rotation circle and the diameter virtual rotation circle also corresponds to a higher removal rate. A small anode edge radius with a small cathode edge radius effectively improves dregs discharge and is an advantage when associated with a high workpiece feed rate. This precision method for the recycling of defective display screen color filters is presented as an effective tool for use in the screen manufacturing process. The defective Indium Tin Oxide thin-film can be removed easily and cleanly in a short time. The complete removal of the ITO layer makes it possible to put these panels back into the production line for reuse with a considerable reduction of both waste and production cost.

Modelling, simulation and verification of the screening process of a swing-bar sieve based on the DEM

NASA Astrophysics Data System (ADS)

Wang, Yang; Yu, Jianqun; Yu, Yajun

2018-05-01

To solve the problems in the DEM simulations of the screening process of a swing-bar sieve, in this paper we propose the real-virtual boundary method to build the geometrical model of the screen deck on a swing-bar sieve. The motion of the swing-bar sieve is modelled by the planer multi-body kinematics. A coupled model of the discrete element method (DEM) with multi-body kinematics (MBK) is presented to simulate the flowing and passing processes of soybean particles on the screen deck. By the comparison of the simulated results with the experimental results of the screening process of the LA-LK laboratory scale swing-bar sieve, the feasibility and validity of the real-virtual boundary method and the coupled DEM-MBK model we proposed in this paper can be verified. This work provides the basis for the optimization design of the swing-bar sieve with circular apertures and complex motion.

Human Factors Virtual Analysis Techniques for NASA's Space Launch System Ground Support using MSFC's Virtual Environments Lab (VEL)

NASA Technical Reports Server (NTRS)

Searcy, Brittani

2017-01-01

Using virtual environments to assess complex large scale human tasks provides timely and cost effective results to evaluate designs and to reduce operational risks during assembly and integration of the Space Launch System (SLS). NASA's Marshall Space Flight Center (MSFC) uses a suite of tools to conduct integrated virtual analysis during the design phase of the SLS Program. Siemens Jack is a simulation tool that allows engineers to analyze human interaction with CAD designs by placing a digital human model into the environment to test different scenarios and assess the design's compliance to human factors requirements. Engineers at MSFC are using Jack in conjunction with motion capture and virtual reality systems in MSFC's Virtual Environments Lab (VEL). The VEL provides additional capability beyond standalone Jack to record and analyze a person performing a planned task to assemble the SLS at Kennedy Space Center (KSC). The VEL integrates Vicon Blade motion capture system, Siemens Jack, Oculus Rift, and other virtual tools to perform human factors assessments. By using motion capture and virtual reality, a more accurate breakdown and understanding of how an operator will perform a task can be gained. By virtual analysis, engineers are able to determine if a specific task is capable of being safely performed by both a 5% (approx. 5ft) female and a 95% (approx. 6'1) male. In addition, the analysis will help identify any tools or other accommodations that may to help complete the task. These assessments are critical for the safety of ground support engineers and keeping launch operations on schedule. Motion capture allows engineers to save and examine human movements on a frame by frame basis, while virtual reality gives the actor (person performing a task in the VEL) an immersive view of the task environment. This presentation will discuss the need of human factors for SLS and the benefits of analyzing tasks in NASA MSFC's VEL.

European Pharmacy Students' Experience With Virtual Patient Technology

PubMed Central

Madeira, Filipe

2012-01-01

Objective. To describe how virtual patients are being used to simulate real-life clinical scenarios in undergraduate pharmacy education in Europe. Methods. One hundred ninety-four participants at the 2011 Congress of the European Pharmaceutical Students Association (EPSA) completed an exploratory cross-sectional survey instrument. Results. Of the 46 universities and 23 countries represented at the EPSA Congress, only 12 students from 6 universities in 6 different countries reported having experience with virtual patient technology. The students were satisfied with the virtual patient technology and considered it more useful as a teaching and learning tool than an assessment tool. Respondents who had not used virtual patient technology expressed support regarding its potential benefits in pharmacy education. French and Dutch students were significantly less interested in virtual patient technology than were their counterparts from other European countries. Conclusion. The limited use of virtual patients in pharmacy education in Europe suggests the need for initiatives to increase the use of virtual patient technology and the benefits of computer-assisted learning in pharmacy education. PMID:22919082

European pharmacy students' experience with virtual patient technology.

PubMed

Cavaco, Afonso Miguel; Madeira, Filipe

2012-08-10

To describe how virtual patients are being used to simulate real-life clinical scenarios in undergraduate pharmacy education in Europe. One hundred ninety-four participants at the 2011 Congress of the European Pharmaceutical Students Association (EPSA) completed an exploratory cross-sectional survey instrument. Of the 46 universities and 23 countries represented at the EPSA Congress, only 12 students from 6 universities in 6 different countries reported having experience with virtual patient technology. The students were satisfied with the virtual patient technology and considered it more useful as a teaching and learning tool than an assessment tool. Respondents who had not used virtual patient technology expressed support regarding its potential benefits in pharmacy education. French and Dutch students were significantly less interested in virtual patient technology than were their counterparts from other European countries. The limited use of virtual patients in pharmacy education in Europe suggests the need for initiatives to increase the use of virtual patient technology and the benefits of computer-assisted learning in pharmacy education.

Validation of virtual reality as a tool to understand and prevent child pedestrian injury.

PubMed

Schwebel, David C; Gaines, Joanna; Severson, Joan

2008-07-01

In recent years, virtual reality has emerged as an innovative tool for health-related education and training. Among the many benefits of virtual reality is the opportunity for novice users to engage unsupervised in a safe environment when the real environment might be dangerous. Virtual environments are only useful for health-related research, however, if behavior in the virtual world validly matches behavior in the real world. This study was designed to test the validity of an immersive, interactive virtual pedestrian environment. A sample of 102 children and 74 adults was recruited to complete simulated road-crossings in both the virtual environment and the identical real environment. In both the child and adult samples, construct validity was demonstrated via significant correlations between behavior in the virtual and real worlds. Results also indicate construct validity through developmental differences in behavior; convergent validity by showing correlations between parent-reported child temperament and behavior in the virtual world; internal reliability of various measures of pedestrian safety in the virtual world; and face validity, as measured by users' self-reported perception of realism in the virtual world. We discuss issues of generalizability to other virtual environments, and the implications for application of virtual reality to understanding and preventing pediatric pedestrian injuries.

Pharmacophore screening of the protein data bank for specific binding site chemistry.

PubMed

Campagna-Slater, Valérie; Arrowsmith, Andrew G; Zhao, Yong; Schapira, Matthieu

2010-03-22

A simple computational approach was developed to screen the Protein Data Bank (PDB) for putative pockets possessing a specific binding site chemistry and geometry. The method employs two commonly used 3D screening technologies, namely identification of cavities in protein structures and pharmacophore screening of chemical libraries. For each protein structure, a pocket finding algorithm is used to extract potential binding sites containing the correct types of residues, which are then stored in a large SDF-formatted virtual library; pharmacophore filters describing the desired binding site chemistry and geometry are then applied to screen this virtual library and identify pockets matching the specified structural chemistry. As an example, this approach was used to screen all human protein structures in the PDB and identify sites having chemistry similar to that of known methyl-lysine binding domains that recognize chromatin methylation marks. The selected genes include known readers of the histone code as well as novel binding pockets that may be involved in epigenetic signaling. Putative allosteric sites were identified on the structures of TP53BP1, L3MBTL3, CHEK1, KDM4A, and CREBBP.

Colorectal Cancer Screening (PDQ®)—Patient Version

Cancer.gov

There are five types of tests that are used to screen for colorectal cancer: fecal occult blood test, sigmoidoscopy, colonoscopy, virtual colonoscopy, and DNA stool test. Learn more about these and other tests in this expert-reviewed summary.

Effect of Virtual Analytical Chemistry Laboratory on Enhancing Student Research Skills and Practices

ERIC Educational Resources Information Center

Bortnik, Boris; Stozhko, Natalia; Pervukhina, Irina; Tchernysheva, Albina; Belysheva, Galina

2017-01-01

This article aims to determine the effect of a virtual chemistry laboratory on university student achievement. The article describes a model of a laboratory course that includes a virtual component. This virtual component is viewed as a tool of student pre-lab autonomous learning. It presents electronic resources designed for a virtual laboratory…

Can we use virtual reality tools in the planning of an experiment?

NASA Astrophysics Data System (ADS)

Kucaba-Pietal, Anna; Szumski, Marek; Szczerba, Piotr

2015-03-01

Virtual reality (VR) has proved to be a particularly useful tool in engineering and design. A related area of aviation in which VR is particularly significant is a flight training, as it requires many hours of practice and using real planes for all training is both expensive and more dangerous. Research conducted at the Rzeszow University of Technology (RUT) showed that virtual reality can be successfully used for planning experiment during a flight tests. Motivation to the study were a wing deformation measurements of PW-6 glider in flight by use Image Pattern Correlation Technique (IPCT) planned within the frame of AIM2 project. The tool VirlIPCT was constructed, which permits to perform virtual IPCT setup on an airplane. Using it, we can test a camera position, camera resolution, pattern application. Moreover performed tests on RUT indicate, that VirlIPCT can be used as a virtual IPCT image generator. This paper presents results of the research on VirlIPCT.

VirSSPA- a virtual reality tool for surgical planning workflow.

PubMed

Suárez, C; Acha, B; Serrano, C; Parra, C; Gómez, T

2009-03-01

A virtual reality tool, called VirSSPA, was developed to optimize the planning of surgical processes. Segmentation algorithms for Computed Tomography (CT) images: a region growing procedure was used for soft tissues and a thresholding algorithm was implemented to segment bones. The algorithms operate semiautomati- cally since they only need seed selection with the mouse on each tissue segmented by the user. The novelty of the paper is the adaptation of an enhancement method based on histogram thresholding applied to CT images for surgical planning, which simplifies subsequent segmentation. A substantial improvement of the virtual reality tool VirSSPA was obtained with these algorithms. VirSSPA was used to optimize surgical planning, to decrease the time spent on surgical planning and to improve operative results. The success rate increases due to surgeons being able to see the exact extent of the patient's ailment. This tool can decrease operating room time, thus resulting in reduced costs. Virtual simulation was effective for optimizing surgical planning, which could, consequently, result in improved outcomes with reduced costs.

Pharmacophore Based 3D-QSAR, Virtual Screening and Docking Studies on Novel Series of HDAC Inhibitors with Thiophen Linker as Anticancer Agents.

PubMed

Patel, Preeti; Singh, Avineesh; Patel, Vijay K; Jain, Deepak K; Veerasamy, Ravichandran; Rajak, Harish

2016-01-01

Histone deacetylase (HDAC) inhibitors can reactivate gene expression and inhibit the growth and survival of cancer cells. To identify the important pharmacophoric features and correlate 3Dchemical structure with biological activity using 3D-QSAR and Pharmacophore modeling studies. The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. Pharmacophore hypothesis represents the 3D arrangement of molecular features necessary for activity. A series of 55 compounds with wellassigned HDAC inhibitory activity were used for 3D-QSAR model development. Best 3D-QSAR model, which is a five partial least square (PLS) factor model with good statistics and predictive ability, acquired Q2 (0.7293), R2 (0.9811), cross-validated coefficient rcv 2=0.9807 and R2 pred=0.7147 with low standard deviation (0.0952). Additionally, the selected pharmacophore model DDRRR.419 was used as a 3D query for virtual screening against the ZINC database. In the virtual screening workflow, docking studies (HTVS, SP and XP) were carried out by selecting multiple receptors (PDB ID: 1T69, 1T64, 4LXZ, 4LY1, 3MAX, 2VQQ, 3C10, 1W22). Finally, six compounds were obtained based on high scoring function (dock score -11.2278-10.2222 kcal/mol) and diverse structures. The structure activity correlation was established using virtual screening, docking, energetic based pharmacophore modelling, pharmacophore, atom based 3D QSAR models and their validation. The outcomes of these studies could be further employed for the design of novel HDAC inhibitors for anticancer activity.

Virtual Reality in Schools: The Ultimate Educational Technology.

ERIC Educational Resources Information Center

Reid, Robert D.; Sykes, Wylmarie

1999-01-01

Discusses the use of virtual reality as an educational tool. Highlights include examples of virtual reality in public schools that lead to a more active learning process, simulated environments, integrating virtual reality into any curriculum, benefits to teachers and students, and overcoming barriers to implementation. (LRW)

Learning Area and Perimeter with Virtual Manipulatives

ERIC Educational Resources Information Center

Bouck, Emily; Flanagan, Sara; Bouck, Mary

2015-01-01

Manipulatives are considered a best practice for educating students with disabilities, but little research exists which examines virtual manipulatives as tool for supporting students in mathematics. This project investigated the use of a virtual manipulative through the National Library of Virtual Manipulatives--polynominoes (i.e., tiles)--as a…

Perceptions of clinical utility of an Augmented Reality musical software among health care professionals.

PubMed

Corrêa, Ana Grasielle Dionísio; de Assis, Gilda Aparecida; do Nascimento, Marilena; de Deus Lopes, Roseli

2017-04-01

Augmented Reality musical software (GenVirtual) is a technology, which primarily allows users to develop music activities for rehabilitation. This study aimed to analyse the perceptions of health care professionals regarding the clinical utility of GenVirtual. A second objective was to identify improvements to GenVirtual software and similar technologies. Music therapists, occupational therapists, physiotherapists and speech and language therapist who assist people with physical and cognitive disabilities were enrolled in three focus groups. The quantitative and qualitative data were collected through inductive thematic analysis. Three main themes were identified: the use of GenVirtual in health care areas; opportunities for realistic application of GenVirtual; and limitations in the use of GenVirtual. The registration units identified were: motor stimulation, cognitive stimulation, verbal learning, recreation activity, musicality, accessibility, motivation, sonic accuracy, interference of lighting, poor sound, children and adults. This research suggested that the GenVirtual is a complementary tool to conventional clinical practice and has great potential to motor and cognitive rehabilitation of children and adults. Implications for Rehabilitation Gaining health professional' perceptions of the Augmented Reality musical game (GenVirtual) give valuable information as to the clinical utility of the software. GenVirtual was perceived as a tool that could be used as enhancing the motor and cognitive rehabilitation process. GenVirtual was viewed as a tool that could enhance clinical practice and communication among various agencies, but it was suggested that it should be used with caution to avoid confusion and replacement of important services.

Simulation of patient encounters using a virtual patient in periodontology instruction of dental students: design, usability, and learning effect in history-taking skills.

PubMed

Schittek Janda, M; Mattheos, N; Nattestad, A; Wagner, A; Nebel, D; Färbom, C; Lê, D-H; Attström, R

2004-08-01

Simulations are important educational tools in the development of health care competence. This study describes a virtual learning environment (VLE) for diagnosis and treatment planning in oral health care. The VLE is a web-based, database application where the learner uses free text communication on the screen to interact with patient data. The VLE contains forms for history taking, clinical images, clinical data and X-rays. After reviewing the patient information, the student proposes therapy and makes prognostic evaluations of the case in free text. A usability test of the application was performed with seven dental students. The usability test showed that the software responded with correct answers to the majority of the free text questions. The application is generic in its basic functions and can be adapted to other dental or medical subject areas. A randomised controlled trial was carried out with 39 students who attended instruction in history taking with problem-based learning cases, lectures and seminars. In addition, 16 of the 39 students were randomly chosen to practise history taking using the virtual patient prior to their first patient encounter. The performance of each student was recorded on video during the patient sessions. The type and order of the questions asked by the student and the degree of empathy displayed towards the patient were analysed systematically on the videos. The data indicate that students who also undertook history taking with a virtual patient asked more relevant questions, spent more time on patient issues, and performed a more complete history interview compared with students who had only undergone standard teaching. The students who had worked with the virtual patient also seemed to have more empathy for the patients than the students who had not. The practising of history taking with a virtual patient appears to improve the capability of dental students to take a relevant oral health history.

Virtual Environment Training: Auxiliary Machinery Room (AMR) Watchstation Trainer.

ERIC Educational Resources Information Center

Hriber, Dennis C.; And Others

1993-01-01

Describes a project implemented at Newport News Shipbuilding that used Virtual Environment Training to improve the performance of submarine crewmen. Highlights include development of the Auxiliary Machine Room (AMR) Watchstation Trainer; Digital Video Interactive (DVI); screen layout; test design and evaluation; user reactions; authoring language;…

Virtual reality interventions for rehabilitation: considerations for developing protocols.

PubMed

Boechler, Patricia; Krol, Andrea; Raso, Jim; Blois, Terry

2009-01-01

This paper is a preliminary report on a work in progress that explores the existence of practice effects in early use of virtual reality environments for rehabilitation purposes and the effects of increases in level of difficulty as defined by rate of on-screen objects.

November 6, 2017, Virtual Meeting on the Charge Questions for the Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (FIFRA SAP) Meeting on Endocrine Disruption

EPA Pesticide Factsheets

This virtual FIFRA SAP meeting will be discus questions on Continuing Development of Alternative High-Throughput Screens to Determine Endocrine Disruption, focusing on Androgen Receptor, Steroidogenesis, and Thyroid Pathways

Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening.

PubMed

Lin, Shih-Hung; Huang, Kao-Jean; Weng, Ching-Feng; Shiuan, David

2015-01-01

Cholesterol plays an important role in living cells. However, a very high level of cholesterol may lead to atherosclerosis. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase is the key enzyme in the cholesterol biosynthesis pathway, and the statin-like drugs are inhibitors of human HMG-CoA reductase (hHMGR). The present study aimed to virtually screen for potential hHMGR inhibitors from natural product to discover hypolipidemic drug candidates with fewer side effects and lesser toxicities. We used the 3D structure 1HWK from the PDB (Protein Data Bank) database of hHMGR as the target to screen for the strongly bound compounds from the traditional Chinese medicine database. Many interesting molecules including polyphenolic compounds, polisubstituted heterocyclics, and linear lipophilic alcohols were identified and their ADMET (absorption, disrtibution, metabolism, excretion, toxicity) properties were predicted. Finally, four compounds were obtained for the in vitro validation experiments. The results indicated that curcumin and salvianolic acid C can effectively inhibit hHMGR, with IC50 (half maximal inhibitory concentration) values of 4.3 µM and 8 µM, respectively. The present study also demonstrated the feasibility of discovering new drug candidates through structure-based virtual screening.

The Reality of Virtual Reality Product Development

NASA Astrophysics Data System (ADS)

Dever, Clark

Virtual Reality and Augmented Reality are emerging areas of research and product development in enterprise companies. This talk will discuss industry standard tools and current areas of application in the commercial market. Attendees will gain insights into how to research, design, and (most importantly) ship, world class products. The presentation will recount the lessons learned to date developing a Virtual Reality tool to solve physics problems resulting from trying to perform aircraft maintenance on ships at sea.

Open Virtual Worlds as Pedagogical Research Tools: Learning from the Schome Park Programme

NASA Astrophysics Data System (ADS)

Twining, Peter; Peachey, Anna

This paper introduces the term Open Virtual Worlds and argues that they are ‘unclaimed educational spaces’, which provide a valuable tool for researching pedagogy. Having explored these claims the way in which Teen Second Life® virtual world was used for pedagogical experimentation in the initial phases of the Schome Park Programme is described. Four sets of pedagogical dimensions that emerged are presented and illustrated with examples from the Schome Park Programme.

The virtual supermarket: An innovative research tool to study consumer food purchasing behaviour

PubMed Central

2011-01-01

Background Economic interventions in the food environment are expected to effectively promote healthier food choices. However, before introducing them on a large scale, it is important to gain insight into the effectiveness of economic interventions and peoples' genuine reactions to price changes. Nonetheless, because of complex implementation issues, studies on price interventions are virtually non-existent. This is especially true for experiments undertaken in a retail setting. We have developed a research tool to study the effects of retail price interventions in a virtual-reality setting: the Virtual Supermarket. This paper aims to inform researchers about the features and utilization of this new software application. Results The Virtual Supermarket is a Dutch-developed three-dimensional software application in which study participants can shop in a manner comparable to a real supermarket. The tool can be used to study several food pricing and labelling strategies. The application base can be used to build future extensions and could be translated into, for example, an English-language version. The Virtual Supermarket contains a front-end which is seen by the participants, and a back-end that enables researchers to easily manipulate research conditions. The application keeps track of time spent shopping, number of products purchased, shopping budget, total expenditures and answers on configurable questionnaires. All data is digitally stored and automatically sent to a web server. A pilot study among Dutch consumers (n = 66) revealed that the application accurately collected and stored all data. Results from participant feedback revealed that 83% of the respondents considered the Virtual Supermarket easy to understand and 79% found that their virtual grocery purchases resembled their regular groceries. Conclusions The Virtual Supermarket is an innovative research tool with a great potential to assist in gaining insight into food purchasing behaviour. The application can be obtained via an URL and is freely available for academic use. The unique features of the tool include the fact that it enables researchers to easily modify research conditions and in this way study different types of interventions in a retail environment without a complex implementation process. Finally, it also maintains researcher independence and avoids conflicts of interest that may arise from industry collaboration. PMID:21787391

The virtual supermarket: an innovative research tool to study consumer food purchasing behaviour.

PubMed

Waterlander, Wilma E; Scarpa, Michael; Lentz, Daisy; Steenhuis, Ingrid H M

2011-07-25

Economic interventions in the food environment are expected to effectively promote healthier food choices. However, before introducing them on a large scale, it is important to gain insight into the effectiveness of economic interventions and peoples' genuine reactions to price changes. Nonetheless, because of complex implementation issues, studies on price interventions are virtually non-existent. This is especially true for experiments undertaken in a retail setting. We have developed a research tool to study the effects of retail price interventions in a virtual-reality setting: the Virtual Supermarket. This paper aims to inform researchers about the features and utilization of this new software application. The Virtual Supermarket is a Dutch-developed three-dimensional software application in which study participants can shop in a manner comparable to a real supermarket. The tool can be used to study several food pricing and labelling strategies. The application base can be used to build future extensions and could be translated into, for example, an English-language version. The Virtual Supermarket contains a front-end which is seen by the participants, and a back-end that enables researchers to easily manipulate research conditions. The application keeps track of time spent shopping, number of products purchased, shopping budget, total expenditures and answers on configurable questionnaires. All data is digitally stored and automatically sent to a web server. A pilot study among Dutch consumers (n = 66) revealed that the application accurately collected and stored all data. Results from participant feedback revealed that 83% of the respondents considered the Virtual Supermarket easy to understand and 79% found that their virtual grocery purchases resembled their regular groceries. The Virtual Supermarket is an innovative research tool with a great potential to assist in gaining insight into food purchasing behaviour. The application can be obtained via an URL and is freely available for academic use. The unique features of the tool include the fact that it enables researchers to easily modify research conditions and in this way study different types of interventions in a retail environment without a complex implementation process. Finally, it also maintains researcher independence and avoids conflicts of interest that may arise from industry collaboration.

Virtual Reality Educational Tool for Human Anatomy.

PubMed

Izard, Santiago González; Juanes Méndez, Juan A; Palomera, Pablo Ruisoto

2017-05-01

Virtual Reality is becoming widespread in our society within very different areas, from industry to entertainment. It has many advantages in education as well, since it allows visualizing almost any object or going anywhere in a unique way. We will be focusing on medical education, and more specifically anatomy, where its use is especially interesting because it allows studying any structure of the human body by placing the user inside each one. By allowing virtual immersion in a body structure such as the interior of the cranium, stereoscopic vision goggles make these innovative teaching technologies a powerful tool for training in all areas of health sciences. The aim of this study is to illustrate the teaching potential of applying Virtual Reality in the field of human anatomy, where it can be used as a tool for education in medicine. A Virtual Reality Software was developed as an educational tool. This technological procedure is based entirely on software which will run in stereoscopic goggles to give users the sensation of being in a virtual environment, clearly showing the different bones and foramina which make up the cranium, and accompanied by audio explanations. Throughout the results the structure of the cranium is described in detailed from both inside and out. Importance of an exhaustive morphological knowledge of cranial fossae is further discussed. Application for the design of microsurgery is also commented.

A Virtual Sensor for Online Fault Detection of Multitooth-Tools

PubMed Central

Bustillo, Andres; Correa, Maritza; Reñones, Anibal

2011-01-01

The installation of suitable sensors close to the tool tip on milling centres is not possible in industrial environments. It is therefore necessary to design virtual sensors for these machines to perform online fault detection in many industrial tasks. This paper presents a virtual sensor for online fault detection of multitooth tools based on a Bayesian classifier. The device that performs this task applies mathematical models that function in conjunction with physical sensors. Only two experimental variables are collected from the milling centre that performs the machining operations: the electrical power consumption of the feed drive and the time required for machining each workpiece. The task of achieving reliable signals from a milling process is especially complex when multitooth tools are used, because each kind of cutting insert in the milling centre only works on each workpiece during a certain time window. Great effort has gone into designing a robust virtual sensor that can avoid re-calibration due to, e.g., maintenance operations. The virtual sensor developed as a result of this research is successfully validated under real conditions on a milling centre used for the mass production of automobile engine crankshafts. Recognition accuracy, calculated with a k-fold cross validation, had on average 0.957 of true positives and 0.986 of true negatives. Moreover, measured accuracy was 98%, which suggests that the virtual sensor correctly identifies new cases. PMID:22163766

A virtual sensor for online fault detection of multitooth-tools.

PubMed

Bustillo, Andres; Correa, Maritza; Reñones, Anibal

2011-01-01

The installation of suitable sensors close to the tool tip on milling centres is not possible in industrial environments. It is therefore necessary to design virtual sensors for these machines to perform online fault detection in many industrial tasks. This paper presents a virtual sensor for online fault detection of multitooth tools based on a bayesian classifier. The device that performs this task applies mathematical models that function in conjunction with physical sensors. Only two experimental variables are collected from the milling centre that performs the machining operations: the electrical power consumption of the feed drive and the time required for machining each workpiece. The task of achieving reliable signals from a milling process is especially complex when multitooth tools are used, because each kind of cutting insert in the milling centre only works on each workpiece during a certain time window. Great effort has gone into designing a robust virtual sensor that can avoid re-calibration due to, e.g., maintenance operations. The virtual sensor developed as a result of this research is successfully validated under real conditions on a milling centre used for the mass production of automobile engine crankshafts. Recognition accuracy, calculated with a k-fold cross validation, had on average 0.957 of true positives and 0.986 of true negatives. Moreover, measured accuracy was 98%, which suggests that the virtual sensor correctly identifies new cases.

Fragment-based virtual screening approach and molecular dynamics simulation studies for identification of BACE1 inhibitor leads.

PubMed

Manoharan, Prabu; Ghoshal, Nanda

2018-05-01

Traditional structure-based virtual screening method to identify drug-like small molecules for BACE1 is so far unsuccessful. Location of BACE1, poor Blood Brain Barrier permeability and P-glycoprotein (Pgp) susceptibility of the inhibitors make it even more difficult. Fragment-based drug design method is suitable for efficient optimization of initial hit molecules for target like BACE1. We have developed a fragment-based virtual screening approach to identify/optimize the fragment molecules as a starting point. This method combines the shape, electrostatic, and pharmacophoric features of known fragment molecules, bound to protein conjugate crystal structure, and aims to identify both chemically and energetically feasible small fragment ligands that bind to BACE1 active site. The two top-ranked fragment hits were subjected for a 53 ns MD simulation. Principle component analysis and free energy landscape analysis reveal that the new ligands show the characteristic features of established BACE1 inhibitors. The potent method employed in this study may serve for the development of potential lead molecules for BACE1-directed Alzheimer's disease therapeutics.

Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening

PubMed Central

Chatterjee, Arindam; Doerksen, Robert J.; Khan, Ikhlas A.

2014-01-01

Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer’s disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening work-flow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2-c]quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP non-competitive CDK5/p25 inhibitors with good CDK2/E selectivity. PMID:25438765

An enantiomer-based virtual screening approach: Discovery of chiral organophosphates as acetyl cholinesterase inhibitors.

PubMed

Zhang, Aiqian; Mu, Yunsong; Wu, Fengchang

2017-04-01

Chiral organophosphates (OPs) have been used widely around the world, very little is known about binding mechanisms with biological macromolecules. An in-depth understanding of the stereo selectivity of human AChE and discovering bioactive enantiomers of OPs can decrease health risks of these chiral chemicals. In the present study, a flexible molecular docking approach was conducted to investigate different binding modes of twelve phosphorus enantiomers. A pharmacophore model was then developed on basis of the bioactive conformations of these compounds. After virtual screening, twenty-four potential bioactive compounds were found, of which three compounds (Ethyl p-nitrophenyl phenylphosphonate (EPN), 1-naphthaleneacetic anhydride and N,4-dimethyl-N-phenyl-benzenesulfonamide) were tested by use of different in vitro assays. S-isomer of EPN was also found to exhibit greater inhibitory activity towards human AChE than the corresponding R-isomer. These findings affirm that stereochemistry plays a crucial role in virtual screening, and provide a new insight into designing safer organ phosphorus pesticides on human health. Copyright © 2017 Elsevier Inc. All rights reserved.

Multiple search methods for similarity-based virtual screening: analysis of search overlap and precision

PubMed Central

2011-01-01

Background Data fusion methods are widely used in virtual screening, and make the implicit assumption that the more often a molecule is retrieved in multiple similarity searches, the more likely it is to be active. This paper tests the correctness of this assumption. Results Sets of 25 searches using either the same reference structure and 25 different similarity measures (similarity fusion) or 25 different reference structures and the same similarity measure (group fusion) show that large numbers of unique molecules are retrieved by just a single search, but that the numbers of unique molecules decrease very rapidly as more searches are considered. This rapid decrease is accompanied by a rapid increase in the fraction of those retrieved molecules that are active. There is an approximately log-log relationship between the numbers of different molecules retrieved and the number of searches carried out, and a rationale for this power-law behaviour is provided. Conclusions Using multiple searches provides a simple way of increasing the precision of a similarity search, and thus provides a justification for the use of data fusion methods in virtual screening. PMID:21824430

Docking and Virtual Screening Strategies for GPCR Drug Discovery.

PubMed

Beuming, Thijs; Lenselink, Bart; Pala, Daniele; McRobb, Fiona; Repasky, Matt; Sherman, Woody

2015-01-01

Progress in structure determination of G protein-coupled receptors (GPCRs) has made it possible to apply structure-based drug design (SBDD) methods to this pharmaceutically important target class. The quality of GPCR structures available for SBDD projects fall on a spectrum ranging from high resolution crystal structures (<2 Å), where all water molecules in the binding pocket are resolved, to lower resolution (>3 Å) where some protein residues are not resolved, and finally to homology models that are built using distantly related templates. Each GPCR project involves a distinct set of opportunities and challenges, and requires different approaches to model the interaction between the receptor and the ligands. In this review we will discuss docking and virtual screening to GPCRs, and highlight several refinement and post-processing steps that can be used to improve the accuracy of these calculations. Several examples are discussed that illustrate specific steps that can be taken to improve upon the docking and virtual screening accuracy. While GPCRs are a unique target class, many of the methods and strategies outlined in this review are general and therefore applicable to other protein families.

Development of a novel class of B-RafV600E-selective inhibitors through virtual screening and hierarchical hit optimization

PubMed Central

Kong, Xiangqian; Qin, Jie; Li, Zeng; Vultur, Adina; Tong, Linjiang; Feng, Enguang; Rajan, Geena; Liu, Shien; Lu, Junyan; Liang, Zhongjie; Zheng, Mingyue; Zhu, Weiliang; Jiang, Hualiang; Herlyn, Meenhard; Liu, Hong; Marmorstein, Ronen; Luo, Cheng

2012-01-01

Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-RafV600E mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we described the development of novel B-RafV600E selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC50 values were identified as B-RafV600E inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds 22f and 22q possess nanomolar IC50 values with selectivity for B-RafV600E in vitro and exclusive cytotoxicity against B-RafV600E harboring cancer cells. PMID:22875039

Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization.

PubMed

Kong, Xiangqian; Qin, Jie; Li, Zeng; Vultur, Adina; Tong, Linjiang; Feng, Enguang; Rajan, Geena; Liu, Shien; Lu, Junyan; Liang, Zhongjie; Zheng, Mingyue; Zhu, Weiliang; Jiang, Hualiang; Herlyn, Meenhard; Liu, Hong; Marmorstein, Ronen; Luo, Cheng

2012-09-28

Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-Raf(V600E) mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we describe the development of novel B-Raf(V600E) selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC(50) values were identified as B-Raf(V600E) inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds 22f and 22q possess nanomolar IC(50) values with selectivity for B-Raf(V600E)in vitro and exclusive cytotoxicity against B-Raf(V600E) harboring cancer cells.

Discovery of nonsteroidal 17beta-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries.

PubMed

Schuster, Daniela; Nashev, Lyubomir G; Kirchmair, Johannes; Laggner, Christian; Wolber, Gerhard; Langer, Thierry; Odermatt, Alex

2008-07-24

17Beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) plays a pivotal role in the local synthesis of the most potent estrogen estradiol. Its expression is a prognostic marker for the outcome of patients with breast cancer and inhibition of 17beta-HSD1 is currently under consideration for breast cancer prevention and treatment. We aimed to identify nonsteroidal 17beta-HSD1 inhibitor scaffolds by virtual screening with pharmacophore models built from crystal structures containing steroidal compounds. The most promising model was validated by comparing predicted and experimentally determined inhibitory activities of several flavonoids. Subsequently, a virtual library of nonsteroidal compounds was screened against the 3D pharmacophore. Analysis of 14 selected compounds yielded four that inhibited the activity of human 17beta-HSD1 (IC 50 below 50 microM). Specificity assessment of identified 17beta-HSD1 inhibitors emphasized the importance of including related short-chain dehydrogenase/reductase (SDR) members to analyze off-target effects. Compound 29 displayed at least 10-fold selectivity over the related SDR enzymes tested.

Virtual Screening Approach of Bacterial Peptide Deformylase Inhibitors Results in New Antibiotics.

PubMed

Merzoug, Amina; Chikhi, Abdelouahab; Bensegueni, Abderrahmane; Boucherit, Hanane; Okay, Sezer

2018-03-01

The increasing resistance of bacteria to antibacterial therapy poses an enormous health problem, it renders the development of new antibacterial agents with novel mechanism of action an urgent need. Peptide deformylase, a metalloenzyme which catalytically removes N-formyl group from N-terminal methionine of newly synthesized polypeptides, is an important target in antibacterial drug discovery. In this study, we report the structure-based virtual screening of ZINC database in order to discover potential hits as bacterial peptide deformylase enzyme inhibitors with more affinity as compared to GSK1322322, previously known inhibitor. After virtual screening, fifteen compounds of the top hits predicted were purchased and evaluated in vitro for their antibacterial activities against one Gram positive (Staphylococcus aureus) and three Gram negative (Escherichia coli, Pseudomonas aeruginosa and Klebsiella. pneumoniae) bacteria in different concentrations by disc diffusion method. Out of these, three compounds, ZINC00039650, ZINC03872971 and ZINC00126407, exhibited significant zone of inhibition. The results obtained were confirmed using the dilution method. Thus, these proposed compounds may aid the development of more efficient antibacterial agents. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Teaching Basic Field Skills Using Screen-Based Virtual Reality Landscapes

NASA Astrophysics Data System (ADS)

Houghton, J.; Robinson, A.; Gordon, C.; Lloyd, G. E. E.; Morgan, D. J.

2016-12-01

We are using screen-based virtual reality landscapes, created using the Unity 3D game engine, to augment the training geoscience students receive in preparing for fieldwork. Students explore these landscapes as they would real ones, interacting with virtual outcrops to collect data, determine location, and map the geology. Skills for conducting field geological surveys - collecting, plotting and interpreting data; time management and decision making - are introduced interactively and intuitively. As with real landscapes, the virtual landscapes are open-ended terrains with embedded data. This means the game does not structure student interaction with the information as it is through experience the student learns the best methods to work successfully and efficiently. These virtual landscapes are not replacements for geological fieldwork rather virtual spaces between classroom and field in which to train and reinforcement essential skills. Importantly, these virtual landscapes offer accessible parallel provision for students unable to visit, or fully partake in visiting, the field. The project has received positive feedback from both staff and students. Results show students find it easier to focus on learning these basic field skills in a classroom, rather than field setting, and make the same mistakes as when learning in the field, validating the realistic nature of the virtual experience and providing opportunity to learn from these mistakes. The approach also saves time, and therefore resources, in the field as basic skills are already embedded. 70% of students report increased confidence with how to map boundaries and 80% have found the virtual training a useful experience. We are also developing landscapes based on real places with 3D photogrammetric outcrops, and a virtual urban landscape in which Engineering Geology students can conduct a site investigation. This project is a collaboration between the University of Leeds and Leeds College of Art, UK, and all our virtual landscapes are freely available online at www.see.leeds.ac.uk/virtual-landscapes/.

Visuo-Haptic Mixed Reality with Unobstructed Tool-Hand Integration.

PubMed

Cosco, Francesco; Garre, Carlos; Bruno, Fabio; Muzzupappa, Maurizio; Otaduy, Miguel A

2013-01-01

Visuo-haptic mixed reality consists of adding to a real scene the ability to see and touch virtual objects. It requires the use of see-through display technology for visually mixing real and virtual objects, and haptic devices for adding haptic interaction with the virtual objects. Unfortunately, the use of commodity haptic devices poses obstruction and misalignment issues that complicate the correct integration of a virtual tool and the user's real hand in the mixed reality scene. In this work, we propose a novel mixed reality paradigm where it is possible to touch and see virtual objects in combination with a real scene, using commodity haptic devices, and with a visually consistent integration of the user's hand and the virtual tool. We discuss the visual obstruction and misalignment issues introduced by commodity haptic devices, and then propose a solution that relies on four simple technical steps: color-based segmentation of the hand, tracking-based segmentation of the haptic device, background repainting using image-based models, and misalignment-free compositing of the user's hand. We have developed a successful proof-of-concept implementation, where a user can touch virtual objects and interact with them in the context of a real scene, and we have evaluated the impact on user performance of obstruction and misalignment correction.

Searching Fragment Spaces with feature trees.

PubMed

Lessel, Uta; Wellenzohn, Bernd; Lilienthal, Markus; Claussen, Holger

2009-02-01

Virtual combinatorial chemistry easily produces billions of compounds, for which conventional virtual screening cannot be performed even with the fastest methods available. An efficient solution for such a scenario is the generation of Fragment Spaces, which encode huge numbers of virtual compounds by their fragments/reagents and rules of how to combine them. Similarity-based searches can be performed in such spaces without ever fully enumerating all virtual products. Here we describe the generation of a huge Fragment Space encoding about 5 * 10(11) compounds based on established in-house synthesis protocols for combinatorial libraries, i.e., we encode practically evaluated combinatorial chemistry protocols in a machine readable form, rendering them accessible to in silico search methods. We show how such searches in this Fragment Space can be integrated as a first step in an overall workflow. It reduces the extremely huge number of virtual products by several orders of magnitude so that the resulting list of molecules becomes more manageable for further more elaborated and time-consuming analysis steps. Results of a case study are presented and discussed, which lead to some general conclusions for an efficient expansion of the chemical space to be screened in pharmaceutical companies.

Sniffing Out Efficacy: Sniffy Lite, a Virtual Animal Lab

ERIC Educational Resources Information Center

Venneman, Sandy S.; Knowles, Laura, Ruth

2005-01-01

We investigated the benefits of using a virtual laboratory, Sniffy Lite CD-ROM (Alloway, Wilson, Graham, & Krames, 2000), as a supplemental teaching tool to present schedules of reinforcement in operant conditioning. Our results suggest that using the virtual laboratory significantly enhanced understanding. Students who used the virtual laboratory…

Ecological validity of virtual reality daily living activities screening for early dementia: longitudinal study.

PubMed

Tarnanas, Ioannis; Schlee, Winfried; Tsolaki, Magda; Müri, René; Mosimann, Urs; Nef, Tobias

2013-08-06

Dementia is a multifaceted disorder that impairs cognitive functions, such as memory, language, and executive functions necessary to plan, organize, and prioritize tasks required for goal-directed behaviors. In most cases, individuals with dementia experience difficulties interacting with physical and social environments. The purpose of this study was to establish ecological validity and initial construct validity of a fire evacuation Virtual Reality Day-Out Task (VR-DOT) environment based on performance profiles as a screening tool for early dementia. The objectives were (1) to examine the relationships among the performances of 3 groups of participants in the VR-DOT and traditional neuropsychological tests employed to assess executive functions, and (2) to compare the performance of participants with mild Alzheimer's-type dementia (AD) to those with amnestic single-domain mild cognitive impairment (MCI) and healthy controls in the VR-DOT and traditional neuropsychological tests used to assess executive functions. We hypothesized that the 2 cognitively impaired groups would have distinct performance profiles and show significantly impaired independent functioning in ADL compared to the healthy controls. The study population included 3 groups: 72 healthy control elderly participants, 65 amnestic MCI participants, and 68 mild AD participants. A natural user interface framework based on a fire evacuation VR-DOT environment was used for assessing physical and cognitive abilities of seniors over 3 years. VR-DOT focuses on the subtle errors and patterns in performing everyday activities and has the advantage of not depending on a subjective rating of an individual person. We further assessed functional capacity by both neuropsychological tests (including measures of attention, memory, working memory, executive functions, language, and depression). We also evaluated performance in finger tapping, grip strength, stride length, gait speed, and chair stands separately and while performing VR-DOTs in order to correlate performance in these measures with VR-DOTs because performance while navigating a virtual environment is a valid and reliable indicator of cognitive decline in elderly persons. The mild AD group was more impaired than the amnestic MCI group, and both were more impaired than healthy controls. The novel VR-DOT functional index correlated strongly with standard cognitive and functional measurements, such as mini-mental state examination (MMSE; rho=0.26, P=.01) and Bristol Activities of Daily Living (ADL) scale scores (rho=0.32, P=.001). Functional impairment is a defining characteristic of predementia and is partly dependent on the degree of cognitive impairment. The novel virtual reality measures of functional ability seem more sensitive to functional impairment than qualitative measures in predementia, thus accurately differentiating from healthy controls. We conclude that VR-DOT is an effective tool for discriminating predementia and mild AD from controls by detecting differences in terms of errors, omissions, and perseverations while measuring ADL functional ability.

Exploring barriers and facilitators to the clinical use of virtual reality for post-stroke unilateral spatial neglect assessment.

PubMed

Ogourtsova, Tatiana; Archambault, Philippe S; Lamontagne, Anouk

2017-11-07

Hemineglect, defined as a failure to attend to the contralesional side of space, is a prevalent and disabling post-stroke deficit. Conventional hemineglect assessments lack sensitivity as they contain mainly non-functional tasks performed in near-extrapersonal space, using static, two-dimensional methods. This is of concern given that hemineglect is a strong predictor for functional deterioration, limited post-stroke recovery, and difficulty in community reintegration. With the emerging field of virtual reality, several virtual tools have been proposed and have reported better sensitivity in neglect-related deficits detection than conventional methods. However, these and future virtual reality-based tools are yet to be implemented in clinical practice. The present study aimed to explore the barriers/facilitators perceived by clinicians in the use of virtual reality for hemineglect assessment; and to identify features of an optimal virtual assessment. A qualitative descriptive process, in the form of focus groups, self-administered questionnaire and individual interviews was used. Two focus groups (n = 11 clinicians) were conducted and experts in the field (n = 3) were individually interviewed. Several barriers and facilitators, including personal, institutional, client suitability, and equipment factors, were identified. Clinicians and experts in the field reported numerous features for the virtual tool optimization. Factors identified through this study lay the foundation for the development of a knowledge translation initiative towards an implementation of a virtual assessment for hemineglect. Addressing the identified barriers/facilitators during implementation and incorporating the optimal features in the design of the virtual assessment could assist and promote its eventual adoption in clinical settings. Implications for rehabilitation A multimodal and active knowledge translation intervention built on the presently identified modifiable factors is suggested to be implemented to support the clinical integration of a virtual reality-based assessment for post-stroke hemineglect. To amplify application and usefulness of a virtual-reality based tool in the assessment of post-stroke hemineglect, optimal features identified in the present study should be incorporated in the design of such technology.

The Virtual Desktop: Options and Challenges in Selecting a Secure Desktop Infrastructure Based on Virtualization

DTIC Science & Technology

2011-10-01

Fortunately, some products offer centralized management and deployment tools for local desktop implementation . Figure 5 illustrates the... implementation of a secure desktop infrastructure based on virtualization. It includes an overview of desktop virtualization, including an in-depth...environment in the data centre, whereas LHVD places it on the endpoint itself. Desktop virtualization implementation considerations and potential

Nutrition screening tools: an analysis of the evidence.

PubMed

Skipper, Annalynn; Ferguson, Maree; Thompson, Kyle; Castellanos, Victoria H; Porcari, Judy

2012-05-01

In response to questions about tools for nutrition screening, an evidence analysis project was developed to identify the most valid and reliable nutrition screening tools for use in acute care and hospital-based ambulatory care settings. An oversight group defined nutrition screening and literature search criteria. A trained analyst conducted structured searches of the literature for studies of nutrition screening tools according to predetermined criteria. Eleven nutrition screening tools designed to detect undernutrition in patients in acute care and hospital-based ambulatory care were identified. Trained analysts evaluated articles for quality using criteria specified by the American Dietetic Association's Evidence Analysis Library. Members of the oversight group assigned quality grades to the tools based on the quality of the supporting evidence, including reliability and validity data. One tool, the NRS-2002, received a grade I, and 4 tools-the Simple Two-Part Tool, the Mini-Nutritional Assessment-Short Form (MNA-SF), the Malnutrition Screening Tool (MST), and Malnutrition Universal Screening Tool (MUST)-received a grade II. The MST was the only tool shown to be both valid and reliable for identifying undernutrition in the settings studied. Thus, validated nutrition screening tools that are simple and easy to use are available for application in acute care and hospital-based ambulatory care settings.

Special Section: New Ways to Detect Colon Cancer 3-D virtual screening now being used

MedlinePlus

... two together," recalls Arie Kaufman, chairman of the computer science department at New York's Stony Brook University. Dr. Kaufman is one of the world's leading researchers in the high-tech medical fields of biomedical visualization, computer graphics, virtual reality, and multimedia. The year was ...

IFPTarget: A Customized Virtual Target Identification Method Based on Protein-Ligand Interaction Fingerprinting Analyses.

PubMed

Li, Guo-Bo; Yu, Zhu-Jun; Liu, Sha; Huang, Lu-Yi; Yang, Ling-Ling; Lohans, Christopher T; Yang, Sheng-Yong

2017-07-24

Small-molecule target identification is an important and challenging task for chemical biology and drug discovery. Structure-based virtual target identification has been widely used, which infers and prioritizes potential protein targets for the molecule of interest (MOI) principally via a scoring function. However, current "universal" scoring functions may not always accurately identify targets to which the MOI binds from the retrieved target database, in part due to a lack of consideration of the important binding features for an individual target. Here, we present IFPTarget, a customized virtual target identification method, which uses an interaction fingerprinting (IFP) method for target-specific interaction analyses and a comprehensive index (Cvalue) for target ranking. Evaluation results indicate that the IFP method enables substantially improved binding pose prediction, and Cvalue has an excellent performance in target ranking for the test set. When applied to screen against our established target library that contains 11,863 protein structures covering 2842 unique targets, IFPTarget could retrieve known targets within the top-ranked list and identified new potential targets for chemically diverse drugs. IFPTarget prediction led to the identification of the metallo-β-lactamase VIM-2 as a target for quercetin as validated by enzymatic inhibition assays. This study provides a new in silico target identification tool and will aid future efforts to develop new target-customized methods for target identification.

Benchmarking Data Sets for the Evaluation of Virtual Ligand Screening Methods: Review and Perspectives.

PubMed

Lagarde, Nathalie; Zagury, Jean-François; Montes, Matthieu

2015-07-27

Virtual screening methods are commonly used nowadays in drug discovery processes. However, to ensure their reliability, they have to be carefully evaluated. The evaluation of these methods is often realized in a retrospective way, notably by studying the enrichment of benchmarking data sets. To this purpose, numerous benchmarking data sets were developed over the years, and the resulting improvements led to the availability of high quality benchmarking data sets. However, some points still have to be considered in the selection of the active compounds, decoys, and protein structures to obtain optimal benchmarking data sets.

Development and experimental test of support vector machines virtual screening method for searching Src inhibitors from large compound libraries

PubMed Central

2012-01-01

Background Src plays various roles in tumour progression, invasion, metastasis, angiogenesis and survival. It is one of the multiple targets of multi-target kinase inhibitors in clinical uses and trials for the treatment of leukemia and other cancers. These successes and appearances of drug resistance in some patients have raised significant interest and efforts in discovering new Src inhibitors. Various in-silico methods have been used in some of these efforts. It is desirable to explore additional in-silico methods, particularly those capable of searching large compound libraries at high yields and reduced false-hit rates. Results We evaluated support vector machines (SVM) as virtual screening tools for searching Src inhibitors from large compound libraries. SVM trained and tested by 1,703 inhibitors and 63,318 putative non-inhibitors correctly identified 93.53%~ 95.01% inhibitors and 99.81%~ 99.90% non-inhibitors in 5-fold cross validation studies. SVM trained by 1,703 inhibitors reported before 2011 and 63,318 putative non-inhibitors correctly identified 70.45% of the 44 inhibitors reported since 2011, and predicted as inhibitors 44,843 (0.33%) of 13.56M PubChem, 1,496 (0.89%) of 168 K MDDR, and 719 (7.73%) of 9,305 MDDR compounds similar to the known inhibitors. Conclusions SVM showed comparable yield and reduced false hit rates in searching large compound libraries compared to the similarity-based and other machine-learning VS methods developed from the same set of training compounds and molecular descriptors. We tested three virtual hits of the same novel scaffold from in-house chemical libraries not reported as Src inhibitor, one of which showed moderate activity. SVM may be potentially explored for searching Src inhibitors from large compound libraries at low false-hit rates. PMID:23173901

Recommendations for evaluation of computational methods

NASA Astrophysics Data System (ADS)

Jain, Ajay N.; Nicholls, Anthony

2008-03-01

The field of computational chemistry, particularly as applied to drug design, has become increasingly important in terms of the practical application of predictive modeling to pharmaceutical research and development. Tools for exploiting protein structures or sets of ligands known to bind particular targets can be used for binding-mode prediction, virtual screening, and prediction of activity. A serious weakness within the field is a lack of standards with respect to quantitative evaluation of methods, data set preparation, and data set sharing. Our goal should be to report new methods or comparative evaluations of methods in a manner that supports decision making for practical applications. Here we propose a modest beginning, with recommendations for requirements on statistical reporting, requirements for data sharing, and best practices for benchmark preparation and usage.

Modeling the Ebolavirus Life Cycle with Transcription and Replication-Competent Viruslike Particle Assays.

PubMed

Biedenkopf, Nadine; Hoenen, Thomas

2017-01-01

Ebolaviruses are the causative agent of a severe hemorrhagic fever with high case fatality rates, for which no approved specific therapy is available. As biosafety level 4 (BSL4) agents, work with live ebolaviruses is restricted to maximum containment laboratories. Transcription and replication-competent viruslike particle (trVLP) systems are reverse genetics-based life cycle modeling systems that allow researchers to model virtually the entire ebolavirus life cycle outside of a maximum containment laboratory. These systems can be used to dissect the virus life cycle, and thus increase our understanding of virus biology, as well as for more applied uses such as the screening and development of novel antivirals, and thus represent powerful tools for work on ebolaviruses.

Detection of flat colorectal polyps at screening CT colonography in comparison with conventional polypoid lesions.

PubMed

Sakamoto, Takashi; Mitsuzaki, Katsuhiko; Utsunomiya, Daisuke; Matsuda, Katsuhiko; Yamamura, Sadahiro; Urata, Joji; Kawakami, Megumi; Yamashita, Yasuyuki

2012-09-01

Although the screening of small, flat polyps is clinically important, the role of CT colonography (CTC) screening in their detection has not been thoroughly investigated. To evaluate the detection capability and usefulness of CTC in the screening of flat and polypoid lesions by comparing CTC with optic colonoscopy findings as the gold standard. We evaluated the CTC detection capability for flat colorectal polyps with a flat surface and a height not exceeding 3 mm (n = 42) by comparing to conventional polypoid lesions (n = 418) according to the polyp diameter. Four types of reconstruction images including multiplanar reconstruction, volume rendering, virtual gross pathology, and virtual endoscopic images were used for visual analysis. We compared the abilities of the four reconstructions for polyp visualization. Detection sensitivity for flat polyps was 31.3%, 44.4%, and 87.5% for lesions measuring 2-3 mm, 4-5 mm, and ≥6 mm, respectively; the corresponding sensitivity for polypoid lesions was 47.6%, 79.0%, and 91.7%. The overall sensitivity for flat lesions (47.6%) was significantly lower than polypoid lesions (64.1%). Virtual endoscopic imaging showed best visualization among the four reconstructions. Colon cancers were detected in eight patients by optic colonoscopy, and CTC detected colon cancers in all eight patients. CTC using 64-row multidetector CT is useful for colon cancer screening to detect colorectal polyps while the detection of small, flat lesions is still challenging.

An Online Image Analysis Tool for Science Education

ERIC Educational Resources Information Center

Raeside, L.; Busschots, B.; Waddington, S.; Keating, J. G.

2008-01-01

This paper describes an online image analysis tool developed as part of an iterative, user-centered development of an online Virtual Learning Environment (VLE) called the Education through Virtual Experience (EVE) Portal. The VLE provides a Web portal through which schoolchildren and their teachers create scientific proposals, retrieve images and…

A Descriptive Study of the Factors Influencing the Degree to Which Fourth-, Fifth-, and Sixth-Grade Virtual Education Students Perceive a Sense of Virtual Community

ERIC Educational Resources Information Center

Gerth, Dana A.

2013-01-01

Review of literature revealed a shortage of research describing the development of K-12 virtual communities and the absence of a tool to measure sense of virtual community in K-12 virtual education students. The purpose of this descriptive, quantitative study was to examine the perception of a sense of virtual community from the perspective of…

Is there a superior simulator for human anatomy education? How virtual dissection can overcome the anatomic and pedagogic limitations of cadaveric dissection.

PubMed

Darras, Kathryn E; de Bruin, Anique B H; Nicolaou, Savvas; Dahlström, Nils; Persson, Anders; van Merriënboer, Jeroen; Forster, Bruce B

2018-03-23

Educators must select the best tools to teach anatomy to future physicians and traditionally, cadavers have always been considered the "gold standard" simulator for living anatomy. However, new advances in technology and radiology have created new teaching tools, such as virtual dissection, which provide students with new learning opportunities. Virtual dissection is a novel way of studying human anatomy through patient computed tomography (CT) scans. Through touchscreen technology, students can work together in groups to "virtually dissect" the CT scans to better understand complex anatomic relationships. This article presents the anatomic and pedagogic limitations of cadaveric dissection and explains what virtual dissection is and how this new technology may be used to overcome these limitations.

Education about Hallucinations Using an Internet Virtual Reality System: A Qualitative Survey

ERIC Educational Resources Information Center

Yellowlees, Peter M.; Cook, James N.

2006-01-01

Objective: The authors evaluate an Internet virtual reality technology as an education tool about the hallucinations of psychosis. Method: This is a pilot project using Second Life, an Internet-based virtual reality system, in which a virtual reality environment was constructed to simulate the auditory and visual hallucinations of two patients…

Approaching Authentic Assessment: Using Virtual School Teachers' Expertise to Develop an Understanding of Full Time K-8 Virtual School Teacher Practices

ERIC Educational Resources Information Center

Seamster, Christina Lambert

2016-01-01

According to Molnar (2014), full time virtual school education lacks a measurement tool that accurately measures effective virtual teacher practice. Using both qualitative and quantitative methods, the current study sought to understand the common practices among full time K-8 virtual school teachers, the extent to which teachers believed such…

Progressive Damage and Failure Analysis of Composite Laminates

NASA Astrophysics Data System (ADS)

Joseph, Ashith P. K.

Composite materials are widely used in various industries for making structural parts due to higher strength to weight ratio, better fatigue life, corrosion resistance and material property tailorability. To fully exploit the capability of composites, it is required to know the load carrying capacity of the parts made of them. Unlike metals, composites are orthotropic in nature and fails in a complex manner under various loading conditions which makes it a hard problem to analyze. Lack of reliable and efficient failure analysis tools for composites have led industries to rely more on coupon and component level testing to estimate the design space. Due to the complex failure mechanisms, composite materials require a very large number of coupon level tests to fully characterize the behavior. This makes the entire testing process very time consuming and costly. The alternative is to use virtual testing tools which can predict the complex failure mechanisms accurately. This reduces the cost only to it's associated computational expenses making significant savings. Some of the most desired features in a virtual testing tool are - (1) Accurate representation of failure mechanism: Failure progression predicted by the virtual tool must be same as those observed in experiments. A tool has to be assessed based on the mechanisms it can capture. (2) Computational efficiency: The greatest advantages of a virtual tools are the savings in time and money and hence computational efficiency is one of the most needed features. (3) Applicability to a wide range of problems: Structural parts are subjected to a variety of loading conditions including static, dynamic and fatigue conditions. A good virtual testing tool should be able to make good predictions for all these different loading conditions. The aim of this PhD thesis is to develop a computational tool which can model the progressive failure of composite laminates under different quasi-static loading conditions. The analysis tool is validated by comparing the simulations against experiments for a selected number of quasi-static loading cases.

Virtual Laboratories and Virtual Worlds

NASA Astrophysics Data System (ADS)

Hut, Piet

2008-05-01

Since we cannot put stars in a laboratory, astrophysicists had to wait till the invention of computers before becoming laboratory scientists. For half a century now, we have been conducting experiments in our virtual laboratories. However, we ourselves have remained behind the keyboard, with the screen of the monitor separating us from the world we are simulating. Recently, 3D on-line technology, developed first for games but now deployed in virtual worlds like Second Life, is beginning to make it possible for astrophysicists to enter their virtual labs themselves, in virtual form as avatars. This has several advantages, from new possibilities to explore the results of the simulations to a shared presence in a virtual lab with remote collaborators on different continents. I will report my experiences with the use of Qwaq Forums, a virtual world developed by a new company (see http://www.qwaq.com).

Seamless 3D interaction for virtual tables, projection planes, and CAVEs

NASA Astrophysics Data System (ADS)

Encarnacao, L. M.; Bimber, Oliver; Schmalstieg, Dieter; Barton, Robert J., III

2000-08-01

The Virtual Table presents stereoscopic graphics to a user in a workbench-like setting. This device shares with other large- screen display technologies (such as data walls and surround- screen projection systems) the lack of human-centered unencumbered user interfaces and 3D interaction technologies. Such shortcomings present severe limitations to the application of virtual reality (VR) technology to time- critical applications as well as employment scenarios that involve heterogeneous groups of end-users without high levels of computer familiarity and expertise. Traditionally such employment scenarios are common in planning-related application areas such as mission rehearsal and command and control. For these applications, a high grade of flexibility with respect to the system requirements (display and I/O devices) as well as to the ability to seamlessly and intuitively switch between different interaction modalities and interaction are sought. Conventional VR techniques may be insufficient to meet this challenge. This paper presents novel approaches for human-centered interfaces to Virtual Environments focusing on the Virtual Table visual input device. It introduces new paradigms for 3D interaction in virtual environments (VE) for a variety of application areas based on pen-and-clipboard, mirror-in-hand, and magic-lens metaphors, and introduces new concepts for combining VR and augmented reality (AR) techniques. It finally describes approaches toward hybrid and distributed multi-user interaction environments and concludes by hypothesizing on possible use cases for defense applications.

Web-based interactive 3D visualization as a tool for improved anatomy learning.

PubMed

Petersson, Helge; Sinkvist, David; Wang, Chunliang; Smedby, Orjan

2009-01-01

Despite a long tradition, conventional anatomy education based on dissection is declining. This study tested a new virtual reality (VR) technique for anatomy learning based on virtual contrast injection. The aim was to assess whether students value this new three-dimensional (3D) visualization method as a learning tool and what value they gain from its use in reaching their anatomical learning objectives. Several 3D vascular VR models were created using an interactive segmentation tool based on the "virtual contrast injection" method. This method allows users, with relative ease, to convert computer tomography or magnetic resonance images into vivid 3D VR movies using the OsiriX software equipped with the CMIV CTA plug-in. Once created using the segmentation tool, the image series were exported in Quick Time Virtual Reality (QTVR) format and integrated within a web framework of the Educational Virtual Anatomy (EVA) program. A total of nine QTVR movies were produced encompassing most of the major arteries of the body. These movies were supplemented with associated information, color keys, and notes. The results indicate that, in general, students' attitudes towards the EVA-program were positive when compared with anatomy textbooks, but results were not the same with dissections. Additionally, knowledge tests suggest a potentially beneficial effect on learning.

An Unbiased Method To Build Benchmarking Sets for Ligand-Based Virtual Screening and its Application To GPCRs

PubMed Central

2015-01-01

Benchmarking data sets have become common in recent years for the purpose of virtual screening, though the main focus had been placed on the structure-based virtual screening (SBVS) approaches. Due to the lack of crystal structures, there is great need for unbiased benchmarking sets to evaluate various ligand-based virtual screening (LBVS) methods for important drug targets such as G protein-coupled receptors (GPCRs). To date these ready-to-apply data sets for LBVS are fairly limited, and the direct usage of benchmarking sets designed for SBVS could bring the biases to the evaluation of LBVS. Herein, we propose an unbiased method to build benchmarking sets for LBVS and validate it on a multitude of GPCRs targets. To be more specific, our methods can (1) ensure chemical diversity of ligands, (2) maintain the physicochemical similarity between ligands and decoys, (3) make the decoys dissimilar in chemical topology to all ligands to avoid false negatives, and (4) maximize spatial random distribution of ligands and decoys. We evaluated the quality of our Unbiased Ligand Set (ULS) and Unbiased Decoy Set (UDS) using three common LBVS approaches, with Leave-One-Out (LOO) Cross-Validation (CV) and a metric of average AUC of the ROC curves. Our method has greatly reduced the “artificial enrichment” and “analogue bias” of a published GPCRs benchmarking set, i.e., GPCR Ligand Library (GLL)/GPCR Decoy Database (GDD). In addition, we addressed an important issue about the ratio of decoys per ligand and found that for a range of 30 to 100 it does not affect the quality of the benchmarking set, so we kept the original ratio of 39 from the GLL/GDD. PMID:24749745

Structure Based Library Design (SBLD) for new 1,4-dihydropyrimidine scaffold as simultaneous COX-1/COX-2 and 5-LOX inhibitors.

PubMed

Lokwani, Deepak; Azad, Rajaram; Sarkate, Aniket; Reddanna, Pallu; Shinde, Devanand

2015-08-01

The various scaffolds containing 1,4-dihydropyrimidine ring were designed by considering the environment of the active site of COX-1/COX-2 and 5-LOX enzymes. The structure-based library design approach, including the focused library design (Virtual Combinatorial Library Design) and virtual screening was used to select the 1,4-dihydropyrimidine scaffold for simultaneous inhibition of both enzyme pathways (COX-1/COX-2 and 5-LOX). The virtual library on each 1,4-dihydropyrimidine scaffold was enumerated in two alternative ways. In first way, the chemical reagents at R groups were filtered by docking of scaffold with single position substitution, that is, only at R1, or R2, or R3, … Rn on COX-2 enzyme using Glide XP docking mode. The structures that do not dock well were removed and the library was enumerated with filtered chemical reagents. In second alternative way, the single position docking stage was bypassed, and the entire library was enumerated using all chemical reagents by docking on the COX-2 enzyme. The entire library of approximately 15,629 compounds obtained from both ways after screening for drug like properties, were further screened for their binding affinity against COX-1 and 5-LOX enzymes using Virtual Screening Workflow. Finally, 142 hits were obtained and divided into two groups based on their binding affinity for COX-1/COX-2 and for both enzyme pathways (COX-1/COX-2 and 5-LOX). The ten molecules were selected, synthesized and evaluated for their COX-1, COX-2 and 5-LOX inhibiting activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

An unbiased method to build benchmarking sets for ligand-based virtual screening and its application to GPCRs.

PubMed

Xia, Jie; Jin, Hongwei; Liu, Zhenming; Zhang, Liangren; Wang, Xiang Simon

2014-05-27

Benchmarking data sets have become common in recent years for the purpose of virtual screening, though the main focus had been placed on the structure-based virtual screening (SBVS) approaches. Due to the lack of crystal structures, there is great need for unbiased benchmarking sets to evaluate various ligand-based virtual screening (LBVS) methods for important drug targets such as G protein-coupled receptors (GPCRs). To date these ready-to-apply data sets for LBVS are fairly limited, and the direct usage of benchmarking sets designed for SBVS could bring the biases to the evaluation of LBVS. Herein, we propose an unbiased method to build benchmarking sets for LBVS and validate it on a multitude of GPCRs targets. To be more specific, our methods can (1) ensure chemical diversity of ligands, (2) maintain the physicochemical similarity between ligands and decoys, (3) make the decoys dissimilar in chemical topology to all ligands to avoid false negatives, and (4) maximize spatial random distribution of ligands and decoys. We evaluated the quality of our Unbiased Ligand Set (ULS) and Unbiased Decoy Set (UDS) using three common LBVS approaches, with Leave-One-Out (LOO) Cross-Validation (CV) and a metric of average AUC of the ROC curves. Our method has greatly reduced the "artificial enrichment" and "analogue bias" of a published GPCRs benchmarking set, i.e., GPCR Ligand Library (GLL)/GPCR Decoy Database (GDD). In addition, we addressed an important issue about the ratio of decoys per ligand and found that for a range of 30 to 100 it does not affect the quality of the benchmarking set, so we kept the original ratio of 39 from the GLL/GDD.

Structural insights into pharmacophore-assisted in silico identification of protein-protein interaction inhibitors for inhibition of human toll-like receptor 4 - myeloid differentiation factor-2 (hTLR4-MD-2) complex.

PubMed

Mishra, Vinita; Pathak, Chandramani

2018-05-29

Toll-like receptor 4 (TLR4) is a member of Toll-Like Receptors (TLRs) family that serves as a receptor for bacterial lipopolysaccharide (LPS). TLR4 alone cannot recognize LPS without aid of co-receptor myeloid differentiation factor-2 (MD-2). Binding of LPS with TLR4 forms a LPS-TLR4-MD-2 complex and directs downstream signaling for activation of immune response, inflammation and NF-κB activation. Activation of TLR4 signaling is associated with various pathophysiological consequences. Therefore, targeting protein-protein interaction (PPI) in TLR4-MD-2 complex formation could be an attractive therapeutic approach for targeting inflammatory disorders. The aim of present study was directed to identify small molecule PPI inhibitors (SMPPIIs) using pharmacophore mapping-based approach of computational drug discovery. Here, we had retrieved the information about the hot spot residues and their pharmacophoric features at both primary (TLR4-MD-2) and dimerization (MD-2-TLR4*) protein-protein interaction interfaces in TLR4-MD-2 homo-dimer complex using in silico methods. Promising candidates were identified after virtual screening, which may restrict TLR4-MD-2 protein-protein interaction. In silico off-target profiling over the virtually screened compounds revealed other possible molecular targets. Two of the virtually screened compounds (C11 and C15) were predicted to have an inhibitory concentration in μM range after HYDE assessment. Molecular dynamics simulation study performed for these two compounds in complex with target protein confirms the stability of the complex. After virtual high throughput screening we found selective hTLR4-MD-2 inhibitors, which may have therapeutic potential to target chronic inflammatory diseases.

Outcomes of Screening Mammography in Elderly Women

DTIC Science & Technology

2004-10-01

program run by the National Health Service (NHS) provides virtually all mammographic screening for women aged 50 or older . 2,3 There are differences also...government-funded National Health Service Breast Screening Program provides free breast cancer screening in the U.K. for women 50 or older . 3, 10 Women aged ...for Public Release; Distribution Unlimited 13. ABSTRACT (Maximum 200 Words) There is uncertainty about whether women older than age 65 should undergo

A combination of 2D similarity search, pharmacophore, and molecular docking techniques for the identification of vascular endothelial growth factor receptor-2 inhibitors.

PubMed

Ai, Guanhua; Tian, Caiping; Deng, Dawei; Fida, Guissi; Chen, Haiyan; Ma, Yuxiang; Ding, Li; Gu, Yueqing

2015-04-01

The human vascular endothelial growth factor receptor-2 (VEGFR-2) has been an attractive target for the inhibition of angiogenesis. In the current study, we used a hybrid protocol of virtual screening methods to retrieve new VEGFR-2 inhibitors from the Zinc-Specs Database (441 574 compounds). The hybrid protocol included the initial screening of candidates by comparing the 2D similarity to five reported top active inhibitors of 13 VEGFR-2 X-ray crystallography structures, followed by the pharmacophore modeling of virtual screening on the basis of receptor-ligand interactions and further narrowing by LibDOCK to obtain the final hits. Two compounds (AN-919/41439526 and AK-968/40939851) with a high libscore were selected as the final hits for a subsequent cell cytotoxicity study. The two compounds screened exerted significant inhibitory effects on the proliferation of cancer cells (U87 and MCF-7). The results indicated that the hybrid procedure is an effective approach for screening specific receptor inhibitors.

Wiki Technology: A Virtual, Cooperative Learning Tool Used to Enhance Student Learning

ERIC Educational Resources Information Center

Barrera, Alessandra L.

2015-01-01

This study demonstrates the use of wiki technology (an editable webpage environment) to provide a virtual, asynchronous collaborative-learning environment for students for the purpose of working on course-content-focused study-guide questions. To analyze the effectiveness of this course tool, students' responses to various qualitative and…

Belle2VR: A Virtual-Reality Visualization of Subatomic Particle Physics in the Belle II Experiment.

PubMed

Duer, Zach; Piilonen, Leo; Glasson, George

2018-05-01

Belle2VR is an interactive virtual-reality visualization of subatomic particle physics, designed by an interdisciplinary team as an educational tool for learning about and exploring subatomic particle collisions. This article describes the tool, discusses visualization design decisions, and outlines our process for collaborative development.

13 Tips for Virtual World Teaching

ERIC Educational Resources Information Center

Villano, Matt

2008-01-01

Multi-user virtual environments (MUVEs) are gaining momentum as the latest and greatest learning tool in the world of education technology. How does one get started with them? How do they work? This article shares 13 secrets from immersive education experts and educators on how to have success in implementing these new tools and technologies on…

Gironacel[R]: A Virtual Tool for Learning Quality Management

ERIC Educational Resources Information Center

Mendez, Empar; Casadesus, Marti; De Ciurana, Quim

2006-01-01

This article describes the Gironacel[R] project--a virtual learning environment produced by the University of Girona. The purpose of this tool is to make it easier for students studying quality management courses within engineering schools to understand what the "quality culture" is and how to implement the ISO 9001:2000 standard in a…

An Experience of CACSD for Networked Control Systems: From Mechatronic Platform Identification to Control Implementation

ERIC Educational Resources Information Center

Losada, Cristina; Espinosa, Felipe; Santos, Carlos; Gálvez, Manuel; Bueno, Emilio J.; Marrón, Marta; Rodríguez, Francisco J.

2016-01-01

Continual advances in information and communication technologies (ICT) are revolutionizing virtual education and bringing new tools on the market that provide virtual solutions to a range of problems. Nevertheless, nonvirtual experimentation using computer-aided control system design tools is still fundamental for future engineers. This paper…

Leadership Trust in Virtual Teams Using Communication Tools: A Quantitative Correlational Study

ERIC Educational Resources Information Center

Clark, Robert Lynn

2014-01-01

The purpose of this quantitative correlational study was to address leadership trust in virtual teams using communication tools in a small south-central, family-owned pharmaceutical organization, with multiple dispersed locations located in the United States. The results of the current research study could assist leaders to develop a communication…

Effects of Collaborative Activities on Group Identity in Virtual World

ERIC Educational Resources Information Center

Park, Hyungsung; Seo, Sumin

2013-01-01

The purpose of this study was to analyze the effects of collaborative activities on group identity in a virtual world such as "Second Life." To achieve this purpose, this study adopted events that promoted participants' interactions using tools inherent in "Second Life." The interactive tools given to the control group in this…

Accuracy of Nutritional Screening Tools in Assessing the Risk of Undernutrition in Hospitalized Children.

PubMed

Huysentruyt, Koen; Devreker, Thierry; Dejonckheere, Joachim; De Schepper, Jean; Vandenplas, Yvan; Cools, Filip

2015-08-01

The aim of the present study was to evaluate the predictive accuracy of screening tools for assessing nutritional risk in hospitalized children in developed countries. The study involved a systematic review of literature (MEDLINE, EMBASE, and Cochrane Central databases up to January 17, 2014) of studies on the diagnostic performance of pediatric nutritional screening tools. Methodological quality was assessed using a modified QUADAS tool. Sensitivity and specificity were calculated for each screening tool per validation method. A meta-analysis was performed to estimate the risk ratio of different screening result categories of being truly at nutritional risk. A total of 11 studies were included on ≥1 of the following screening tools: Pediatric Nutritional Risk Score, Screening Tool for the Assessment of Malnutrition in Paediatrics, Paediatric Yorkhill Malnutrition Score, and Screening Tool for Risk on Nutritional Status and Growth. Because of variation in reference standards, a direct comparison of the predictive accuracy of the screening tools was not possible. A meta-analysis was performed on 1629 children from 7 different studies. The risk ratio of being truly at nutritional risk was 0.349 (95% confidence interval [CI] 0.16-0.78) for children in the low versus moderate screening category and 0.292 (95% CI 0.19-0.44) in the moderate versus high screening category. There is insufficient evidence to choose 1 nutritional screening tool over another based on their predictive accuracy. The estimated risk of being at "true nutritional risk" increases with each category of screening test result. Each screening category should be linked to a specific course of action, although further research is needed.

Virtual Environment TBI Screen (VETS)

DTIC Science & Technology

2014-10-01

balance challenges performed on a modified Wii Balance Board . Implementation of this device will enhance current approaches in TBI and mild TBI (i.e...TBI) screen (VETS) device in measuring standing balance . This system consists of software, a Wii balance board , and a large screen television that...Validate Wii ™ Balance Board relative to NeuroCom forceplate ! Running Wii Balance Board validation protocol. ! Milestone Achieved:

Virtual Astronomy: The Legacy of the Virtual Astronomical Observatory

NASA Astrophysics Data System (ADS)

Hanisch, Robert J.; Berriman, G. B.; Lazio, J.; Szalay, A. S.; Fabbiano, G.; Plante, R. L.; McGlynn, T. A.; Evans, J.; Emery Bunn, S.; Claro, M.; VAO Project Team

2014-01-01

Over the past ten years, the Virtual Astronomical Observatory (VAO, http://usvao.org) and its predecessor, the National Virtual Observatory (NVO), have developed and operated a software infrastructure consisting of standards and protocols for data and science software applications. The Virtual Observatory (VO) makes it possible to develop robust software for the discovery, access, and analysis of astronomical data. Every major publicly funded research organization in the US and worldwide has deployed at least some components of the VO infrastructure; tens of thousands of VO-enabled queries for data are invoked daily against catalog, image, and spectral data collections; and groups within the community have developed tools and applications building upon the VO infrastructure. Further, NVO and VAO have helped ensure access to data internationally by co-founding the International Virtual Observatory Alliance (IVOA, http://ivoa.net). The products of the VAO are being archived in a publicly accessible repository. Several science tools developed by the VAO will continue to be supported by the organizations that developed them: the Iris spectral energy distribution package (SAO), the Data Discovery Tool (STScI/MAST, HEASARC), and the scalable cross-comparison service (IPAC). The final year of VAO is focused on development of the data access protocol for data cubes, creation of Python language bindings to VO services, and deployment of a cloud-like data storage service that links to VO data discovery tools (SciDrive). We encourage the community to make use of these tools and services, to extend and improve them, and to carry on with the vision for virtual astronomy: astronomical research enabled by easy access to distributed data and computational resources. Funding for VAO development and operations has been provided jointly by NSF and NASA since May 2010. NSF funding will end in September 2014, though with the possibility of competitive solicitations for VO-based tool development. NASA intends to maintain core VO services such as the resource registry (the index of VO-accessible data collections), monitoring services, and a website as part of the remit of HEASARC, IPAC (IRSA, NED), and MAST.

Efficient hit-finding approaches for histone methyltransferases: the key parameters.

PubMed

Ahrens, Thomas; Bergner, Andreas; Sheppard, David; Hafenbradl, Doris

2012-01-01

For many novel epigenetics targets the chemical ligand space and structural information were limited until recently and are still largely unknown for some targets. Hit-finding campaigns are therefore dependent on large and chemically diverse libraries. In the specific case of the histone methyltransferase G9a, the authors have been able to apply an efficient process of intelligent selection of compounds for primary screening, rather than screening the full diverse deck of 900 000 compounds to identify hit compounds. A number of different virtual screening methods have been applied for the compound selection, and the results have been analyzed in the context of their individual success rates. For the primary screening of 2112 compounds, a FlashPlate assay format and full-length histone H3.1 substrate were employed. Validation of hit compounds was performed using the orthogonal fluorescence lifetime technology. Rated by purity and IC(50) value, 18 compounds (0.9% of compound screening deck) were finally considered validated primary G9a hits. The hit-finding approach has led to novel chemotypes being identified, which can facilitate hit-to-lead projects. This study demonstrates the power of virtual screening technologies for novel, therapeutically relevant epigenetics protein targets.

Third-Graders Learn about Fractions Using Virtual Manipulatives: A Classroom Study

ERIC Educational Resources Information Center

Reimer, Kelly; Moyer, Patricia S.

2005-01-01

With recent advances in computer technology, it is no surprise that the manipulation of objects in mathematics classrooms now includes the manipulation of objects on the computer screen. These objects, referred to as "virtual manipulatives," are essentially replicas of physical manipulatives placed on the World Wide Web in the form of computer…

Active Learning Environments with Robotic Tangibles: Children's Physical and Virtual Spatial Programming Experiences

ERIC Educational Resources Information Center

Burleson, Winslow S.; Harlow, Danielle B.; Nilsen, Katherine J.; Perlin, Ken; Freed, Natalie; Jensen, Camilla Nørgaard; Lahey, Byron; Lu, Patrick; Muldner, Kasia

2018-01-01

As computational thinking becomes increasingly important for children to learn, we must develop interfaces that leverage the ways that young children learn to provide opportunities for them to develop these skills. Active Learning Environments with Robotic Tangibles (ALERT) and Robopad, an analogous on-screen virtual spatial programming…

The Role of Interactional Quality in Learning from Touch Screens during Infancy: Context Matters.

PubMed

Zack, Elizabeth; Barr, Rachel

2016-01-01

Interactional quality has been shown to enhance learning during book reading and play, but has not been examined during touch screen use. Learning to apply knowledge from a touch screen is complex for infants because it involves transfer of learning between a two-dimensional (2D) screen and three-dimensional (3D) object in the physical world. This study uses a touch screen procedure to examine interactional quality measured via maternal structuring, diversity of maternal language, and dyadic emotional responsiveness and infant outcomes during a transfer of learning task. Fifty 15-month-old infants and their mothers participated in this semi-naturalistic teaching task. Mothers were given a 3D object, and a static image of the object presented on a touch screen. Mothers had 5 min to teach their infant that a button on the real toy works in the same way as a virtual button on the touch screen (or vice versa). Overall, 64% of infants learned how to make the button work, transferring learning from the touch screen to the 3D object or vice versa. Infants were just as successful in the 3D to 2D transfer direction as they were in the 2D to 3D transfer direction. A cluster analysis based on emotional responsiveness, the proportion of diverse maternal verbal input, and amount of maternal structuring resulted in two levels of interactional quality: high quality and moderate quality. A logistic regression revealed the level of interactional quality predicted infant transfer. Infants were 19 times more likely to succeed and transfer learning between the touch screen and real object if they were in a high interactional quality dyad, even after controlling for infant activity levels. The present findings suggest that interactional quality between mother and infant plays an important role in making touch screens effective teaching tools for infants' learning.

The Role of Interactional Quality in Learning from Touch Screens during Infancy: Context Matters

PubMed Central

Zack, Elizabeth; Barr, Rachel

2016-01-01

Interactional quality has been shown to enhance learning during book reading and play, but has not been examined during touch screen use. Learning to apply knowledge from a touch screen is complex for infants because it involves transfer of learning between a two-dimensional (2D) screen and three-dimensional (3D) object in the physical world. This study uses a touch screen procedure to examine interactional quality measured via maternal structuring, diversity of maternal language, and dyadic emotional responsiveness and infant outcomes during a transfer of learning task. Fifty 15-month-old infants and their mothers participated in this semi-naturalistic teaching task. Mothers were given a 3D object, and a static image of the object presented on a touch screen. Mothers had 5 min to teach their infant that a button on the real toy works in the same way as a virtual button on the touch screen (or vice versa). Overall, 64% of infants learned how to make the button work, transferring learning from the touch screen to the 3D object or vice versa. Infants were just as successful in the 3D to 2D transfer direction as they were in the 2D to 3D transfer direction. A cluster analysis based on emotional responsiveness, the proportion of diverse maternal verbal input, and amount of maternal structuring resulted in two levels of interactional quality: high quality and moderate quality. A logistic regression revealed the level of interactional quality predicted infant transfer. Infants were 19 times more likely to succeed and transfer learning between the touch screen and real object if they were in a high interactional quality dyad, even after controlling for infant activity levels. The present findings suggest that interactional quality between mother and infant plays an important role in making touch screens effective teaching tools for infants’ learning. PMID:27625613

Distance underestimation in virtual space is sensitive to gender but not activity-passivity or mode of interaction.

PubMed

Foreman, Nigel; Sandamas, George; Newson, David

2004-08-01

Four groups of undergraduates (half of each gender) experienced a movement along a corridor containing three distinctive objects, in a virtual environment (VE) with wide-screen projection. One group simulated walking along the virtual corridor using a proprietary step-exercise device. A second group moved along the corridor in conventional flying mode, depressing a keyboard key to initiate continuous forward motion. Two further groups observed the walking and flying participants, by viewing their progress on the screen. Participants then had to walk along a real equivalent but empty corridor, and indicate the positions of the three objects. All groups underestimated distances in the real corridor, the greatest underestimates occurring for the middle distance object. Males' underestimations were significantly lower than females' at all distances. However, there was no difference between the active participants and passive observers, nor between walking and flying conditions.

Library Virtual Tours: A Case Study

ERIC Educational Resources Information Center

Ashmore, Beth; Grogg, Jill E.

2004-01-01

Virtual tours delivered via the Web have become a common tool for both instruction and outreach. This article is a case study of the creation of a virtual tour for a university library and is intended to provide others interested in creating a virtual tour of their library the opportunity to learn from the mistakes and successes of fellow…

The BRIGHTEN program: implementation and evaluation of a program to bridge resources of an interdisciplinary geriatric health team via electronic networking.

PubMed

Emery, Erin E; Lapidos, Stan; Eisenstein, Amy R; Ivan, Iulia I; Golden, Robyn L

2012-12-01

To demonstrate the feasibility of the BRIGHTEN Program (Bridging Resources of an Interdisciplinary Geriatric Health Team via Electronic Networking), an interdisciplinary team intervention for assessing and treating older adults for depression in outpatient primary and specialty medical clinics. The BRIGHTEN team collaborates "virtually" to review patient assessment results, develop a treatment plan, and refer to appropriate team members for follow-up care. Older adults in 9 academic medical center clinics and 2 community-based clinics completed screening forms for symptoms of depression and anxiety. Those with positive screens engaged in comprehensive assessment with the BRIGHTEN Program Coordinator; the BRIGHTEN virtual team provided treatment recommendations based on the results of assessment. A collaborative treatment plan was developed with each participant, who was then connected to appropriate services. Two thousand four hundred twenty-two older adults were screened in participating clinics over a 40-month period. Eight hundred fifty-nine older adults screened positive, and 150 elected to enroll in BRIGHTEN. From baseline to 6 months, significant improvements were found in depression symptoms (Geriatric Depression Scale, p < .01) and general mental health (SF-12 Mental Component, p < .01). The BRIGHTEN Program demonstrated that an interdisciplinary virtual team linked with outpatient medical clinics can be an effective, nonthreatening, and seamless approach to enable older adults to access treatment for depression.

Homology modeling and virtual screening of inhibitors against TEM- and SHV-type-resistant mutants: A multilayer filtering approach.

PubMed

Baig, Mohammad H; Balaramnavar, Vishal M; Wadhwa, Gulshan; Khan, Asad U

2015-01-01

TEM and SHV are class-A-type β-lactamases commonly found in Escherichia coli and Klebsiella pneumoniae. Previous studies reported S130G and K234R mutations in SHVs to be 41- and 10-fold more resistant toward clavulanic acid than SHV-1, respectively, whereas TEM S130G and R244S also showed the same level of resistance. These selected mutants confer higher level of resistance against clavulanic acid. They also show little susceptibility against other commercially available β-lactamase inhibitors. In this study, we have used docking-based virtual screening approach in order to screen potential inhibitors against some of the major resistant mutants of SHV and TEM types β-lactamase. Two different inhibitor-resistant mutants from SHV and TEM were selected. Moreover, we have retained the active site water molecules within each enzyme. Active site water molecules were placed within modeled structure of the mutant whose structure was unavailable with protein databank. The novelty of this work lies in the use of multilayer virtual screening approach for the prediction of best and accurate results. We are reporting five inhibitors on the basis of their efficacy against all the selected resistant mutants. These inhibitors were selected on the basis of their binding efficacies and pharmacophore features. © 2015 International Union of Biochemistry and Molecular Biology, Inc.

Discovery of novel mGluR1 antagonists: a multistep virtual screening approach based on an SVM model and a pharmacophore hypothesis significantly increases the hit rate and enrichment factor.

PubMed

Li, Guo-Bo; Yang, Ling-Ling; Feng, Shan; Zhou, Jian-Ping; Huang, Qi; Xie, Huan-Zhang; Li, Lin-Li; Yang, Sheng-Yong

2011-03-15

Development of glutamate non-competitive antagonists of mGluR1 (Metabotropic glutamate receptor subtype 1) has increasingly attracted much attention in recent years due to their potential therapeutic application for various nervous disorders. Since there is no crystal structure reported for mGluR1, ligand-based virtual screening (VS) methods, typically pharmacophore-based VS (PB-VS), are often used for the discovery of mGluR1 antagonists. Nevertheless, PB-VS usually suffers a lower hit rate and enrichment factor. In this investigation, we established a multistep ligand-based VS approach that is based on a support vector machine (SVM) classification model and a pharmacophore model. Performance evaluation of these methods in virtual screening against a large independent test set, M-MDDR, show that the multistep VS approach significantly increases the hit rate and enrichment factor compared with the individual SB-VS and PB-VS methods. The multistep VS approach was then used to screen several large chemical libraries including PubChem, Specs, and Enamine. Finally a total of 20 compounds were selected from the top ranking compounds, and shifted to the subsequent in vitro and in vivo studies, which results will be reported in the near future. Copyright © 2011 Elsevier Ltd. All rights reserved.