The benefits of in silico modeling to identify possible small-molecule drugs and their off-target interactions

Accepted for publication in a future issue of Future Medicinal Chemistry.The research into the use of small molecules as drugs continues to be a key driver in the development of molecular databases, computer-aided drug design software and collaborative platforms. The evolution of computational approaches is driven by the essential criteria that a drug molecule has to fulfill, from the affinity to targets to minimal side effects while having adequate absorption, distribution, metabolism, and excretion (ADME) properties. A combination of ligand- and structure-based drug development approaches is already used to obtain consensus predictions of small molecule activities and their off-target interactions. Further integration of these methods into easy-to-use workflows informed by systems biology could realize the full potential of available data in the drug discovery and reduce the attrition of drug candidates.Peer reviewe

Data Leak Detection As a Service: Challenges and Solutions

We describe a network-based data-leak detection (DLD) technique, the main feature of which is that the detection does not require the data owner to reveal the content of the sensitive data. Instead, only a small amount of specialized digests are needed. Our technique – referred to as the fuzzy fingerprint – can be used to detect accidental data leaks due to human errors or application flaws. The privacy-preserving feature of our algorithms minimizes the exposure of sensitive data and enables the data owner to safely delegate the detection to others.We describe how cloud providers can offer their customers data-leak detection as an add-on service with strong privacy guarantees. We perform extensive experimental evaluation on the privacy, efficiency, accuracy and noise tolerance of our techniques. Our evaluation results under various data-leak scenarios and setups show that our method can support accurate detection with very small number of false alarms, even when the presentation of the data has been transformed. It also indicates that the detection accuracy does not degrade when partial digests are used. We further provide a quantifiable method to measure the privacy guarantee offered by our fuzzy fingerprint framework

STCP: Receiver-agnostic Communication Enabled by Space-Time Cloud Pointers

Department of Electrical and Computer Engineering (Computer Engineering)During the last decade, mobile communication technologies have rapidly evolved and ubiquitous network connectivity is nearly achieved. However, we observe that there are critical situations where none of the existing mobile communication technologies is usable. Such situations are often found when messages need to be delivered to arbitrary persons or devices that are located in a specific space at a specific time. For instance at a disaster scene, current communication methods are incapable of delivering messages of a rescuer to the group of people at a specific area even when their cellular connections are alive because the rescuer cannot specify the receivers of the messages. We name this as receiver-unknown problem and propose a viable solution called SpaceMessaging. SpaceMessaging adopts the idea of Post-it by which we casually deliver our messages to a person who happens to visit a location at a random moment. To enable SpaceMessaging, we realize the concept of posting messages to a space by implementing cloud-pointers at a cloud server to which messages can be posted and from which messages can fetched by arbitrary mobile devices that are located at that space. Our Android-based prototype of SpaceMessaging, which particularly maps a cloud-pointer to a WiFi signal fingerprint captured from mobile devices, demonstrates that it first allows mobile devices to deliver messages to a specific space and to listen to the messages of a specific space in a highly accurate manner (with more than 90% of Recall)

Eliciting the Functional Taxonomy from protein annotations and taxa

The advances of omics technologies have triggered the production of an enormous volume of data coming from thousands of species. Meanwhile, joint international efforts like the Gene Ontology (GO) consortium have worked to provide functional information for a vast amount of proteins. With these data available, we have developed FunTaxIS, a tool that is the first attempt to infer functional taxonomy (i.e. how functions are distributed over taxa) combining functional and taxonomic information. FunTaxIS is able to define a taxon specific functional space by exploiting annotation frequencies in order to establish if a function can or cannot be used to annotate a certain species. The tool generates constraints between GO terms and taxa and then propagates these relations over the taxonomic tree and the GO graph. Since these constraints nearly cover the whole taxonomy, it is possible to obtain the mapping of a function over the taxonomy. FunTaxIS can be used to make functional comparative analyses among taxa, to detect improper associations between taxa and functions, and to discover how functional knowledge is either distributed or missing. A benchmark test set based on six different model species has been devised to get useful insights on the generated taxonomic rules

Gypsum-DL: an open-source program for preparing small-molecule libraries for structure-based virtual screening

Computational techniques such as structure-based virtual screening require carefully prepared 3D models of potential small-molecule ligands. Though powerful, existing commercial programs for virtual-library preparation have restrictive and/or expensive licenses. Freely available alternatives, though often effective, do not fully account for all possible ionization, tautomeric, and ring-conformational variants. We here present Gypsum-DL, a free, robust open-source program that addresses these challenges. As input, Gypsum-DL accepts virtual compound libraries in SMILES or flat SDF formats. For each molecule in the virtual library, it enumerates appropriate ionization, tautomeric, chiral, cis/trans isomeric, and ring-conformational forms. As output, Gypsum-DL produces an SDF file containing each molecular form, with 3D coordinates assigned. To demonstrate its utility, we processed 1558 molecules taken from the NCI Diversity Set VI and 56,608 molecules taken from a Distributed Drug Discovery (D3) combinatorial virtual library. We also used 4463 high-quality protein-ligand complexes from the PDBBind database to show that Gypsum-DL processing can improve virtual-screening pose prediction. Gypsum-DL is available free of charge under the terms of the Apache License, Version 2.0

Software Tools and Approaches for Compound Identification of LC-MS/MS Data in Metabolomics.

The annotation of small molecules remains a major challenge in untargeted mass spectrometry-based metabolomics. We here critically discuss structured elucidation approaches and software that are designed to help during the annotation of unknown compounds. Only by elucidating unknown metabolites first is it possible to biologically interpret complex systems, to map compounds to pathways and to create reliable predictive metabolic models for translational and clinical research. These strategies include the construction and quality of tandem mass spectral databases such as the coalition of MassBank repositories and investigations of MS/MS matching confidence. We present in silico fragmentation tools such as MS-FINDER, CFM-ID, MetFrag, ChemDistiller and CSI:FingerID that can annotate compounds from existing structure databases and that have been used in the CASMI (critical assessment of small molecule identification) contests. Furthermore, the use of retention time models from liquid chromatography and the utility of collision cross-section modelling from ion mobility experiments are covered. Workflows and published examples of successfully annotated unknown compounds are included

The zombies strike back: Towards client-side beef detection

A web browser is an application that comes bundled with every consumer operating system, including both desktop and mobile platforms. A modern web browser is complex software that has access to system-level features, includes various plugins and requires the availability of an Internet connection. Like any multifaceted software products, web browsers are prone to numerous vulnerabilities. Exploitation of these vulnerabilities can result in destructive consequences ranging from identity theft to network infrastructure damage. BeEF, the Browser Exploitation Framework, allows taking advantage of these vulnerabilities to launch a diverse range of readily available attacks from within the browser context. Existing defensive approaches aimed at hardening network perimeters and detecting common threats based on traffic analysis have not been found successful in the context of BeEF detection. This paper presents a proof-of-concept approach to BeEF detection in its own operating environment – the web browser – based on global context monitoring, abstract syntax tree fingerprinting and real-time network traffic analysis

Updates in metabolomics tools and resources: 2014-2015

Data processing and interpretation represent the most challenging and time-consuming steps in high-throughput metabolomic experiments, regardless of the analytical platforms (MS or NMR spectroscopy based) used for data acquisition. Improved machinery in metabolomics generates increasingly complex datasets that create the need for more and better processing and analysis software and in silico approaches to understand the resulting data. However, a comprehensive source of information describing the utility of the most recently developed and released metabolomics resources—in the form of tools, software, and databases—is currently lacking. Thus, here we provide an overview of freely-available, and open-source, tools, algorithms, and frameworks to make both upcoming and established metabolomics researchers aware of the recent developments in an attempt to advance and facilitate data processing workflows in their metabolomics research. The major topics include tools and researches for data processing, data annotation, and data visualization in MS and NMR-based metabolomics. Most in this review described tools are dedicated to untargeted metabolomics workflows; however, some more specialist tools are described as well. All tools and resources described including their analytical and computational platform dependencies are summarized in an overview Table