Publications

Publication date: October 23, 2024

Our colleagues at the Institute of Molecular Genetics (IMG) in Prague, CZ, and the EU-OPENSCREEN central office in Berlin, DE, have a new publication out explaining the rationale, design and curation of the European Chemical Biology Database (ECBD), the central open-access repository for all screening data generated within EU-OPENSCREEN ERIC. 

The ECBD is designed according to the FAIR data principles (findable, accessible, interoperable, and reusable) and contains both positive and negative activity data from EU-OPENSCREEN compound screening and bioprofiling campaigns. It thus serves as a rich characterization of chemical space and a uniquely valuable resource to the global scientific community.

Read the full text here: https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkae904/7832351?utm_source=advanceaccess&utm_campaign=nar&utm_medium=email

Publication date: October 4, 2024

Our colleagues at our screening partner site Fraunhofer ITMP report on an effort to identify and validate inhibitors of SARS-CoV-2 papain-like protease PLpro activity. They utilized three repurposing libraries for this study, including the EU-OPENSCREEN bioactives collection.

Read the full text here: https://pubs.acs.org/doi/10.1021/acsptsci.4c00325

Publication date: September 2024

EU-OPENSCREEN's partner site Fraunhofer ITMP in Germany  has created a knowledge graph generator (KGG) leveraged on the BY-COVID project and is ready to share their toolkit with you.
The KGG is developed for a broad spectrum of researchers and scientists, especially for those who are into pre-clinical drug discovery, understanding disease mechanisms/comorbidity and drug-repurposing. Although KGG is a programmatic tool, it comes with a user-friendly interface to take just a couple of input from a user to run the underlying scripts and methods.
To read the publication and get some hands-on experience with creating your own KG, please follow this link: https://www.infectious-diseases-toolkit.org/showcase/knowledge-graph-generator

Publication date: September 11, 2024

The new publication from our partner site in Latvia, the Latvian Institute of Organic Synthesis in Riga, focusses on the viral RNA capping mechanism, a key strategy for evading host immunity. Coronaviruses, including SARS-CoV-2, use two methylating enzymes—nsp14 and nsp16-nsp10—to mimic the natural eukaryotic mRNA cap, making viral RNA less detectable by the immune system.
The study utilized X-ray crystallography to analyse how SAM analogues bind to the nsp16-nsp10 complex, resulting in eleven 3D crystal structures. This revealed different conformations of the molecules and confirmed that dual-site targeting (binding both SAM and RNA sites) enhances inhibitory potential.
These findings offer new possibilities for antiviral drug development, targeting this essential viral process to hinder immune evasion and combat infections like COVID-19.
Read the full publication here: https://pubmed.ncbi.nlm.nih.gov/39258386/

Publication date: July 18, 2024

Activin receptor-like kinases 1–7 (ALK1–7) regulate a complex network of SMAD-independent as well as SMAD-dependent signaling pathways. One of the widely used inhibitors for functional investigations of these processes, in particular for bone morphogenetic protein (BMP) signaling, is LDN-193189. However, LDN-193189 has insufficient kinome-wide selectivity complicating its use in cellular target validation assays. Herein, we report the identification and comprehensive characterization of two chemically distinct highly selective inhibitors of ALK1 and ALK2, M4K2234 and MU1700, along with their negative controls. We show that both MU1700 and M4K2234 efficiently block the BMP pathway via selective in cellulo inhibition of ALK1/2 kinases and exhibit favorable in vivo profiles in mice. MU1700 is highly brain penetrant and shows remarkably high accumulation in the brain. These high-quality orthogonal chemical probes offer the selectivity required to become widely used tools for in vitro and in vivo investigation of BMP signaling.

Read the full paper here: https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00629 

Publication date: June 2024

Publication in co-operation with our partner site ITMP Fraunhofer

In June 2022, EU-OS came to the decision to make public a solubility data set of 100+K compounds obtained from several of the EU-OS proprietary screening compound collections. Leveraging on the interest of SLAS for screening scientific development it was decided to launch a joint EUOS-SLAS competition within the chemoinformatics and machine learning (ML) communities.

The competition was open to real world computation experts, for the best, most predictive, classification model of compound solubility. The aim of the competition was multiple: from a practical side, the winning model should then serve as a cornerstone for future solubility predictions having used the largest training set so far publicly available. From a higher project perspective, the intent was to focus the energies and experiences, even if professionally not precisely coming from Pharma R&D; to address the issue of how to predict compound solubility.

Here we report how the competition was ideated and the practical aspects of conducting it within the Kaggle framework, leveraging of the versatility and the open-source nature of this data science platform. Consideration on results and challenges encountered have been also examined..

Read the full paper here: https://www.sciencedirect.com/science/article/pii/S2472555224000170?dgcid=rss_sd_all

Publication date: May 8, 2024

Our partners at the Institute of Medical Biology PAS in Lodz, Poland, have co-authored a paper with several chemistry and life sciences collaborators on the topic of boron neutron capture therapy (BNCT), an emerging anti-tumour therapeutic approach.

In this publication, the authors propose a set of in vitro bioprofiling assays and methods to identify compounds which represent promising boron carriers for BNCT.

Available online: https://www.mdpi.com/2073-4409/13/10/798

Publication date: April 2024

Publication of our partner site University de Santiago de Compostela (USC)

The purpose of the protocol reported in this work by our partner site University de Santiago de Compostela (USC) is the solubility profiling of large chemical libraries using nephelometry. This technique allows the qualitative classification of compounds as highly, moderately, or poorly water-soluble. The described methodology is not intended to yield quantitative solubility values of the studied compounds but can be used as a primary solubility assessment of large chemical libraries, to guide hit prioritization after High Throughput Screening (HTS) campaigns.

Read the full paper here: https://www.sciencedirect.com/science/article/pii/S247255522400011X

Publication date: February 13,  2024

This publication results from the EU-OPENSCREEN/SLAS kaggle challenge aimed to facilitate the development of reliable algorithms to predict the aqueous solubility of small molecules using experimental data from 100 K compounds. In total, hundred teams took part in the challenge to predict low, medium and highly soluble compounds as measured by the nephelometry assay. This article describes the winning model, which was developed using the publicly available Online CHEmical database and Modeling environment (OCHEM) available on the website https://ochem.eu/article/27

Read the full paper here: https://www.sciencedirect.com/science/article/pii/S2472555224000170?dgcid=rss_sd_all

Publication date: February 12,  2024

The paper describes the computational design, quality control and use case screenings of the EU-OPENSCREEN Fragment Screening Library (EFSL), composed of 1,056 mini and small chemical fragments selected from a substructure analysis of our EU-OPENSCREEN European Chemical Biology Library (ECBL).

Under the framework of the EU-OPENSCREEN-DRIVE project, the EFSL poised to ECBL compounds was designed to facilitate rapid fragment-to-lead progression. The EFSL is the result of the successful collaboration between EU-OPENSCREEN and structural biology experts from the Instruct-ERIC and iNEXT-Discovery consortia.

Read the full paper here: https://pubs.rsc.org/en/Content/ArticleLanding/2024/MD/D3MD00724C

Publication date: November 15, 2023

The main goals and challenges for the life science communities in the Open Science framework are to increase reuse and sustainability of data resources, software tools, and workflows, especially in large‐scale data‐driven research and computational analyses. The paper presents key findings, procedures, effective measures and recommendations for generating and establishing sustainable life science resources based on the collaborative, cross‐disciplinary work done within the EOSC‐Life (European Open Science Cloud for Life Sciences) consortium. Bringing together 13 European life science research infrastructures, it has laid the foundation for an open, digital space to support biological and medical research. Using lessons learned from 27 selected projects, the organisational, technical, financial and legal/ethical challenges are described that represent the main barriers to sustainability in the life sciences. It is shown how EOSC‐Life provides a model for sustainable data management according to FAIR (findability, accessibility, interoperability, and reusability) principles, including solutions for sensitive‐ and industry‐related resources, by means of cross‐disciplinary training and best practices sharing. Finally, it is illustrated how data harmonisation and collaborative work facilitates interoperability of tools, data, solutions and leads to a better understanding of concepts, semantics and functionalities in the life sciences.

Read the full paper here: https://www.embopress.org/doi/full/10.15252/embj.2023115008

Publication date: April 14, 2021

Fragment-based screening is an approach to identify building blocks of the future drug molecule, observing how they interact with the protein under study, contextualizing those interactions, and providing starting points for molecules that directly influence the biology of the protein. New research published by EU-OPENSCREEN collaborators at the XChem platform at Diamond performed a crystallographic fragment screen of the macrodomain part of the Nsp3 gene product that SARS-CoV-2 uses to suppress the host cell’s natural antiviral response.

This study discovered 234 fragment compounds that directly bind to sites of interest on the surface of the protein, and that can be used by researchers and pharmaceutical companies to design compounds that could be developed into antiviral drugs. 

DOI 10.1126/sciadv.abf8711

Publication date: March 11, 2021

Authors: Maria Kuzikov*, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
   

Abstract

Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro and have identified 62 additional compounds with IC50 values below 1 μM and profiled their selectivity toward chymotrypsin and 3CL-Pro from the Middle East respiratory syndrome virus. A subset of eight inhibitors showed anticytopathic effect in a Vero-E6 cell line, and the compounds thioguanosine and MG-132 were analyzed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Å, showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

https://doi.org/10.1021/acsptsci.0c00216

Publication date: March 4, 2021

Authors: AlessandraSilvestri¹, FranciscaVicente²,  María J.Vicent³,  BahneStechmann¹,  WolfgangFecke¹

¹ EU-OPENSCREEN ERIC, Berlin, Germany

² Fundación MEDINA, Granada, Spain

³ Polymer Therapeutics Lab and Screening Platform, Príncipe Felipe Research Centre, Valencia, Spain

DOI:https://doi.org/10.1016/j.drudis.2021.02.024
    

Abstract

In this review, we provide an overview of recent publications in the field of HTS with complex cellular models, explain the potential of these approaches, and highlight gaps that still need to be addressed. Moreover, we bring the attention of cellular biology and medicinal chemistry groups to collaborative initiatives, such as EU-OPENSCREEN ERIC, which can efficiently support researchers from academia and industry to easily access such complex assay formats in state-of-the-art chemical biology platforms. Such collaborative approaches can accelerate the drug discovery process and allow for a more efficient development of new technologies and their adaptation onto screening platforms. This will lead to the production of more physiologically relevant results that, in turn, can be more easily translated into clinical therapies.

The success of preclinical drug discovery strongly relies on the ability of experimental models to resemble human pathophysiology. The number of compounds receiving approval for clinical use is limited, and this has led to the development of more physiologically relevant cellular models aimed at making preclinical results more prone to be successfully translated into clinical use. In this review, we summarize the technologies available in the field of high-throughput screening (HTS) using complex cellular models, and describe collaborative initiatives, such as EU-OPENSCREEN, which can efficiently support researchers to easily access state-of-the-art chemical biology platforms for improving the drug discovery process and allow for a more efficient development of new technologies and their adaptation onto screening platforms. This will lead to the production of more physiologically relevant results that, in turn, can be more easily translated into clinical therapies.
 

Publication date: January 7, 2019

Authors: Philip Brennecke, Dace Rasina, Oscar Aubi, Katja Herzog, Johannes Landskron, Bastien Cautain, Francisca Vicente, Jordi Quintana, Jordi Mestres, Bahne Stechmann, Bernhard Ellinger, Jose Brea, Jacek L. Kolanowski, Radosław Pilarski, Mar Orzaez, Antonio Pineda-Lucena, Luca Laraia, Faranak Nami, Piotr Zielenkiewicz, Kamil Paruch, Espen Hansen, Jens P. von Kries, Martin Neuenschwander, Edgar Specker, Petr Bartunek, Sarka Simova, Zbigniew Leśnikowski, Stefan Krauss, Lari Lehtiö, Ursula Bilitewski, Mark Brönstrup, Kjetil Taskén, Aigars Jirgensons, Heiko Lickert, Mads H. Clausen, Jeanette H. Andersen, Maria J. Vicent, Olga Genilloud, Aurora Martinez, Marc Nazaré, Wolfgang Fecke, Philip Gribbon

DOI: https://doi.org/10.1177/2472555218816276

Abstract: 

Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN’s compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.