Application of particle swarm optimization to understand the mechanism of action of allosteric inhibitors of the enzyme HSD17ß13.

Understanding a drug candidate's mechanism of action is crucial for its further development. However, kinetic schemes are often complex and multi-parametric, especially for proteins in oligomerization equilibria. Here, we demonstrate the use of particle swarm optimization (PSO) as a method to select between different sets of parameters that are too far apart in the parameter space to be found by conventional approaches. PSO is based upon the swarming of birds: each bird in the flock assesses multiple landing spots while at the same time sharing that information with its neighbors. We applied this approach to the kinetics of HSD17ß13 enzyme inhibitors, which displayed unusually large thermal shifts. Thermal shift data for HSD17ß13 indicated that the inhibitor shifted the oligomerization equilibrium toward the dimeric state. Validation of the PSO approach was provided by experimental mass photometry data. These results encourage further exploration of multi-parameter optimization algorithms as tools in drug discovery.

MichelaNglo: sculpting protein views on web pages without coding.

MOTIVATION: The sharing of macromolecular structural information online by scientists is predominantly performed via 2D static images, since the embedding of interactive 3D structures in webpages is non-trivial. Whilst the technologies to do so exist, they are often only implementable with significant web coding experience. RESULTS: Michelaɴɢʟo is an accessible and open-source web-based application that supports the generation, customization and sharing of interactive 3D macromolecular visualizations for digital media without requiring programming skills. A PyMOL file, PDB file, PDB identifier code or protein/gene name can be provided to form the basis of visualizations using the NGL JavaScript library. Hyperlinks that control the view can be added to text within the page. Protein-coding variants can be highlighted to support interpretation of their potential functional consequences. The resulting visualizations and text can be customized and shared, as well as embedded within existing websites by following instructions and using a self-contained download. Michelaɴɢʟo allows researchers to move away from static images and instead engage, describe and explain their protein to a wider audience in a more interactive fashion. AVAILABILITY AND IMPLEMENTATION: Michelaɴɢʟo is hosted at michelanglo.sgc.ox.ac.uk. The Python code is freely available at https://github.com/thesgc/MichelaNGLo, along with documentations about its implementation.

A genetics-led approach defines the drug target landscape of 30 immune-related traits.

Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection1. Drug targets with genetic support are more likely to be therapeutically valid2,3, but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging4-6. Here, we show that integration of functional genomic and immune-related annotations, together with knowledge of network connectivity, maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level. We demonstrate how our genetics-led drug target prioritization approach (the priority index) successfully identifies current therapeutics, predicts activity in high-throughput cellular screens (including L1000, CRISPR, mutagenesis and patient-derived cell assays), enables prioritization of under-explored targets and allows for determination of target-level trait relationships. The priority index is an open-access, scalable system accelerating early-stage drug target selection for immune-mediated disease.

UbiHub: a data hub for the explorers of ubiquitination pathways.

MOTIVATION: Protein ubiquitination plays a central role in important cellular machineries such as protein degradation or chromatin-mediated signaling. With the recent discovery of the first potent ubiquitin-specific protease inhibitors, and the maturation of proteolysis targeting chimeras as promising chemical tools to exploit the ubiquitin-proteasome system, protein target classes associated with ubiquitination pathways are becoming the focus of intense drug-discovery efforts. RESULTS: We have developed UbiHub, an online resource that can be used to visualize a diverse array of biological, structural and chemical data on phylogenetic trees of human protein families involved in ubiquitination signaling, including E3 ligases and deubiquitinases. This interface can inform target prioritization and drug design, and serves as a navigation tool for medicinal chemists, structural and cell biologists exploring ubiquitination pathways. AVAILABILITY AND IMPLEMENTATION: https://ubihub.thesgc.org.

SATurn: a modular bioinformatics framework for the design of robust maintainable web-based and standalone applications.

Summary: SATurn is a modular, open-source, bioinformatics platform designed to specifically address the problems of maintenance and longevity commonly associated with the development of simple tools funded by academic research grants. Applications developed in SATurn can be deployed as web-based tools, standalone applications or hybrid tools which have the benefits of both. Within the Structural Genomics Consortium we have utilized SATurn to create a bioinformatics portal which routinely supports a diverse group of scientists including those interested in structural biology, cloning, glycobiology and chemical biology. Availability and implementation: https://github.com/ddamerell53/SATurn. Supplementary information: Supplementary data are available at Bioinformatics online.

Donated chemical probes for open science.

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (https://openscienceprobes.sgc-frankfurt.de/). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project.

Annotation of glycomics MS and MS/MS spectra using the GlycoWorkbench software tool.

The GlycoWorkbench software tool allows users to semiautomatically annotate glycomics MS and MS/MS spectra and MS glycoproteomics spectra. The GlycanBuilder software tool is embedded within GlycoWorkbench allowing users to draw glycan structures and export images of the drawn structures. This chapter demonstrates to users how to draw glycan structures within GlycoWorkbench using the GlycanBuilder software tool. This chapter also demonstrates how to use GlycoWorkbench to import MS and MS/MS glycomics spectra and use the cascading annotation feature to annotate both the MS and MS/MS spectra with a single command.

Toolboxes for a standardised and systematic study of glycans.

BACKGROUND: Recent progress in method development for characterising the branched structures of complex carbohydrates has now enabled higher throughput technology. Automation of structure analysis then calls for software development since adding meaning to large data collections in reasonable time requires corresponding bioinformatics methods and tools. Current glycobioinformatics resources do cover information on the structure and function of glycans, their interaction with proteins or their enzymatic synthesis. However, this information is partial, scattered and often difficult to find to for non-glycobiologists. METHODS: Following our diagnosis of the causes of the slow development of glycobioinformatics, we review the "objective" difficulties encountered in defining adequate formats for representing complex entities and developing efficient analysis software. RESULTS: Various solutions already implemented and strategies defined to bridge glycobiology with different fields and integrate the heterogeneous glyco-related information are presented. CONCLUSIONS: Despite the initial stage of our integrative efforts, this paper highlights the rapid expansion of glycomics, the validity of existing resources and the bright future of glycobioinformatics.

The GlycanBuilder and GlycoWorkbench glycoinformatics tools: updates and new developments.

During the EUROCarbDB project our group developed the GlycanBuilder and GlycoWorkbench glycoinformatics tools. This short communication summarizes the capabilities of these two tools and updates which have been made since the original publications in 2007 and 2008. GlycanBuilder is a tool that allows for the fast and intuitive drawing of glycan structures; this tool can be used standalone, embedded in web pages and can also be integrated into other programs. GlycoWorkbench has been designed to semi-automatically annotate glycomics data. This tool can be used to annotate mass spectrometry (MS) and MS/MS spectra of free oligosaccharides, N and O-linked glycans, GAGs (glycosaminoglycans) and glycolipids, as well as MS spectra of glycoproteins.

EUROCarbDB: An open-access platform for glycoinformatics.

The EUROCarbDB project is a design study for a technical framework, which provides sophisticated, freely accessible, open-source informatics tools and databases to support glycobiology and glycomic research. EUROCarbDB is a relational database containing glycan structures, their biological context and, when available, primary and interpreted analytical data from high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance experiments. Database content can be accessed via a web-based user interface. The database is complemented by a suite of glycoinformatics tools, specifically designed to assist the elucidation and submission of glycan structure and experimental data when used in conjunction with contemporary carbohydrate research workflows. All software tools and source code are licensed under the terms of the Lesser General Public License, and publicly contributed structures and data are freely accessible. The public test version of the web interface to the EUROCarbDB can be found at http://www.ebi.ac.uk/eurocarb.

ProtorP: a protein-protein interaction analysis server.

SUMMARY: The PROTORP server analyses protein-protein associations in 3D structures. The server calculates a series of physical and chemical parameters of the protein interaction sites that contribute to the binding energy of the association. These parameters include, size and shape, intermolecular bonding, residue and atom composition and secondary structure contributions. The server is flexible, in that it allows users to analyse individual protein associations or large datasets of associations deposited in the PDB, or upload and analyse proprietary files. The properties calculated can be compared with parameter distributions for non-homologous datasets of different classes of protein associations provided on the server website. The server provides an efficient way of characterizing protein-protein associations of new or existing proteins, and a means of putting these values in the context of previously observed associations. AVAILABILITY: http://www.bioinformatics.sussex.ac.uk/protorp