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29 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-1-Macromolecular Crystallography (fixed wavelength)	Fragment-based design of targeted covalent inhibitors: the scope and limitation of linking approaches Levente Kollár , Levente M. Mihalovits , Dávid Bajusz , Damijan Knez , József Simon , Blake H. Balcomb , Daren Fearon , Stanislav Gobec , György M. Keserű Chemmedchem 21 DOI: 10.1002/cmdc.202501108 Diamond Proposal Number(s): [27963] Open Access Show Abstract ▼ Abstract: Linking of fragments in neighboring binding sites is one of the optimization strategies in fragment-based drug discovery, where additive or even more substantial bioactivity improvements can be realized. However, such efforts present a considerable challenge when one fragment binds covalently to the target protein, as small modifications can influence the correct positioning of the covalent warhead toward the targeted nucleophilic residue. Here, we present a case study of fragment linking that yielded single-digit micromolar, covalent inhibitors of the SARS-CoV-2 main protease, starting from fragments that were inactive in the biochemical assay. Using structural information from a recent, high-throughput crystallographic fragment screen, we show that the success of fragment linking in the design of targeted covalent inhibitors is heavily impacted by several factors, including the warhead type, the labeling chemistry, and even subtle changes in the designed linker. Notably, we observe that induced fit effects might override the original fragment orientations in the linked molecule, highlighting the need for reliable structure verification, especially in consecutive rounds of fragment elaboration.	May 2026
I04-Macromolecular Crystallography	Identification of the piperidyl urea derivative BAY-439 as a potent and selective inhibitor of human phospholipase A2 Group V (hPLA2-G5) for the treatment of inflammatory pain Gernot Langer , Nico Bräuer , Daryl Walter , Stuart Flanagan , Olivier Rémi Barbeau , Wei Tsung Yau , James Jenkins , Dennis Wegener , Daren Fearon , Anne-Marie Coelho , Benjamin Bader , Anders Friberg , Hartmut Beck , Vera Pütter , Frank Sacher Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.6c00488 Show Abstract ▼ Abstract: Human Phospholipase A2 Group V (hPLA2-G5) is elevated in inflammatory conditions and promotes neutrophil and macrophage recruitment. Its enzymatic activity activates lipid receptors and cytosolic phospholipase A2 (cPLA2), leading to arachidonic acid release and PGE2 production─key mediators of chronic inflammation. Thus, hPLA2-G5 represents a promising therapeutic target for diseases with inflammatory pain, such as in endometriosis─a highly debilitating disease characterized by the ectopic growth of endometriotic cells in the abdominal cavity. High-throughput and fragment-based screening identified structurally related small molecule hits. Optimization of the physicochemical and pharmacokinetic properties of the HTS hit led to the identification of BAY-439, a potent and selective hPLA2-G5 inhibitor with single-digit nanomolar activity. Accepted as a donated chemical probe by the Structural Genomics Consortium, both BAY-439 and the inactive negative probe BAY-163 are freely available as valuable pharmacological tools to investigate the role of hPLA2-G5 both under physiological and pathological conditions.	May 2026
	A computational community blind challenge on pan-coronavirus drug discovery data Hugo Macdermott-Opeskin , Jenke Scheen , Cas Wognum , Joshua T. Horton , Devany West , Alexander M. Payne , Maria A. Castellanos , Sean Colby , Edward Griffen , David Cousins , Jessica Stacey , Lauren Reid , Jasmin Cara Aschenbrenner , Daren Fearon , Blake H. Balcomb , Peter Marples , Charles W. E. Tomlinson , Ryan Lithgo , Andre S. Godoy , Max Winokan , Noa Lahav , Shirley Duberstein , Honore Etsmoberg , Lu Zhu , Andrew Quirke , Mohamed Iliyas Abdul Haleem , Irfan Alibay , Gunjan Baid , Benjamin Birnbaum , Kevin P. Bishop , Hugo Bohorquez , Ashmita Bose , C. J. Brown , Jackson Burns , Lianjin Cai , Ruel Cedeno , Stephane De Cesco , Vladimir Chupakhin , Finlay Clark , Daniel J. Cole , Carles Corbi-Verge , Muhammad Danial , Alec Davi , Wim Dehaen , Niklas Piet Doering , Alexis Dougha , Marie-Pierre Dréanic , Bryce Eakin , Anatol Ehrlich , Rokas Elijosius , Jozef Fülöp , Anthony Gitter , Kenneth Goossens , Yaowen Gu , Teresa Head-Gordon , Laurent Hoffer , Johan Hofmans , Ellena Jiang , Benjamin Kaminow , Sina Khosravi , Asma Feriel Khoualdi , Eelke Bart Lenselink , Zhirong Liu , Yue Liu , Sijie Liu , Yizhou Ma , Patrick Maher , Imke Mayer , Oscar Mendez-Lucio , Antonia S. J. S. Mey , Julien Michel , Floriane Montanari , Taoyu Niu , Ryusei Ogino , Ashok Palaniappan , Xiaolin Pan , Auro Patnaik , Long-Hung Pham , Luis Pinto , Justin Purnomo , Alex Rich , Lars Schaaf , Christoph Schran , Rajeev Kumar Singh , Mounika Srilakshmi , Satya Pratik Srivastava , Kunyang Sun , Zhaoxi Sun , Valerij Talagayev , Balamurugan Thirukonda Subramanian Balakrishnan , Ida Titus , Alexandre Tkatchenko , Wojtek Treyde , Giovanni Tricarico , Austin Tripp , Nopsinth Vithayapalert , Yingze Wang , Azmine Toushik Wasi , Steffen Wedig , Gerhard Wolber , Bofei Xu , Weijun Zhou , Frank Von Delft , John D. Chodera Journal Of Chemical Information And Modeling 40 DOI: 10.1021/acs.jcim.5c02106 Show Abstract ▼ Abstract: Computational blind challenges offer critical, unbiased opportunities to assess and accelerate scientific progress, as demonstrated by a breadth of breakthroughs over the past decade. We report the outcomes and key insights from an open science community blind challenge focused on computational methods in drug discovery, using lead optimization data from the AI-driven Structure-enabled Antiviral Platform Discovery Consortium’s pan-coronavirus antiviral discovery program, in partnership with Polaris and the OpenADMET project. This collaborative initiative invited global participants from both academia and industry to develop and apply computational methods to predict the biochemical potency and crystallographic ligand poses of small molecules against key coronavirus targets, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) main protease (Mpro), as well as multiple ADMET assay end points, using previously undisclosed comprehensive experimental drug discovery data sets as benchmarks. By evaluating submissions across multiple tasks and compounds, we established performance leaderboards and conducted meta-analyses to assess methodological strengths, common pitfalls, and areas for improvement. This analysis provides a foundation for best practices in real-world machine learning evaluation, grounded in community-driven benchmarking. We also highlight how next-generation platforms, such as Polaris, enable rigorous challenge design, embedded evaluation frameworks, and broad community engagement. This paper reports the collective findings of the challenge, offering a high-level overview of the data, evaluation infrastructure, and top-performing strategies. We further provide context and support for the accompanying papers authored by the challenge participants in this special issue, which explore individual approaches in greater depth. Together, these contributions aim to advance reproducible, trustworthy, and high-impact computational methods in drug discovery, and to explore best practices and pitfalls in future blind challenge design and execution, including planned initiatives for the OpenADMET project.	Feb 2026
I04-1-Macromolecular Crystallography (fixed wavelength)	Combined crystallographic fragment screening and deep mutational scanning enable discovery of Zika virus NS2B-NS3 protease inhibitors Xiaomin Ni , R. Blake Richardson , Andre Schutzer Godoy , Matteo P. Ferla , Caroline Kikawa , Jenke Scheen , William W. Hannon , Eda Capkin , Noa Lahav , Blake H. Balcomb , Peter G. Marples , Michael Fairhead , Siyi Wang , Eleanor P. Williams , Charles W. E. Tomlinson , Jasmin C. Aschenbrenner , Ryan Lithgo , Max Winokan , Charline Giroud , Isabela Dolci , Rafaela Sachetto Fernandes , Glaucius Oliva , Anu V. Chandran , Mary-Ann Xavier , Martin A. Walsh , Warren Thompson , Jesse D. Bloom , Nathaniel T. Kenton , Alpha A. Lee , Annette Von Delft , Haim Barr , Karla Kirkegaard , Lizbe Koekemoer , Daren Fearon , Matthew J. Evans , Frank Von Delft Nature Communications 16 DOI: 10.1038/s41467-025-63602-z Diamond Proposal Number(s): [32627] Open Access Show Abstract ▼ Abstract: The Zika viral protease NS2B-NS3 is essential for the cleavage of viral polyprotein precursor into individual structural and non-structural (NS) proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 46 fragments with diverse scaffolds are identified to bind in the active site of the protease, with another 6 fragments observed in a potential allosteric site. To identify binding sites that are intolerant to mutation and thus suppress the outgrowth of viruses resistant to inhibitors developed from bound fragments, we perform deep mutational scanning of the NS2B-NS3 protease. Merging fragment hits yields an extensive set of ‘mergers’, defined as synthetically accessible compounds that recapitulate constellations of observed fragment-protein interactions. In addition, the highly sociable fragment hits enable rapid exploration of chemical space via algorithmic calculation and thus yield diverse possible starting points. In this work, we maximally explore the binding opportunities to NS2B-NS3 protease, facilitating its resistance-resilient antiviral development.	Oct 2025
I04-1-Macromolecular Crystallography (fixed wavelength)	Crystallographic fragment screening of the Dengue virus polymerase reveals multiple binding sites for the development of non-nucleoside antiflavivirals Manisha Saini , Jasmin C. Aschenbrenner , Francesc Xavier Ruiz , Ashima Chopra , Anu V. Chandran , Peter G. Marples , Blake H. Balcomb , Daren Fearon , Frank Von Delft , Eddy Arnold Journal Of Medicinal Chemistry 276 DOI: 10.1021/acs.jmedchem.5c01014 Diamond Proposal Number(s): [32633] Open Access Show Abstract ▼ Abstract: Dengue viruses (DENVs) infect approximately 400 million people each year, and currently, there are no effective therapeutics available. To explore potential starting points for antiviral drug development, we conducted a large-scale crystallographic fragment screen targeting the RNA-dependent RNA polymerase (RdRp) domain of the nonstructural protein 5 (NS5) from DENV serotype 2. Our screening, which involved 1108 fragments, identified 60 hit compounds across various known binding sites, including the active site, N pocket, and RNA tunnel. Additionally, we discovered a novel binding site and a fragment-binding hot spot in thumb site II. These structural findings open amenable avenues for developing non-nucleoside inhibitors and offer valuable insights for future structure-based drug design aimed at DENV and other flaviviral RdRps.	Sep 2025
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Crystal structure of fatty acid thioesterase A bound by 129 fragments provides diverse development opportunities Ekaterina Kot , Matteo P. Ferla , Patricia H. Hollinshead , Charles W. E. Tomlinson , Daren Fearon , Jasmin C. Aschenbrenner , Lizbe Koekemoer , Max Winokan , Michael Fairhead , Xiaomin Ni , Rod Chalk , Katherine S. England , Laura Ortega Varga , Mark Greer Montgomery , Nicholas P. Mulholland , Frank Von Delft Pest Management Science 148 DOI: 10.1002/ps.70199 Diamond Proposal Number(s): [28172, 34598, 30602, 36049] Open Access Show Abstract ▼ Abstract: BACKGROUND: In order to alleviate the growing issue of herbicide resistance, diversification of the herbicide portfolio is necessary. A promising yet underutilized mode-of-action is the inhibition of fatty acid thioesterases (FATs), which terminate de novo fatty acid (FA) biosynthesis by releasing FAs from acyl carrier protein (ACP) cofactors. These enzymes impact plant growth and sterility by determining the amount and length of FAs present. In this study we report a crystallographic fragment screening approach for the identification of novel chemical matter targeting FATs. RESULTS: We have solved the crystal structure of Arabidopsis thaliana FatA to 1.5 Å and conducted a crystallographic fragment screen which identified 129 unique fragments bound in 141 different poses. Ten fragments demonstrated on-scale potency, two of these exploiting different interactions to known herbicides. Elaboration of one of the fragments resulted in an improvement of affinity from ~20 μm to ~90 nm KD. Finally, superposition of our crystal structures revealed that some fragments exploit large conformational changes in the substrate binding site. CONCLUSION: We have fully enabled FatA as a target for rapid, rational hit-to-lead development, with robust structural, biophysical and biochemical assays. We provide a set of fragment hits which represent diverse, novel scaffolds that both recapitulate interactions made by current herbicides, and also target novel regions within the active and dimer sites. Our fragments can be readily merged and allow for effective catalogue-based structure–activity relationship (SAR) exploration. Together these data will accelerate the development of novel, alternative herbicides to combat herbicide resistance.	Sep 2025
I04-1-Macromolecular Crystallography (fixed wavelength)	Crystallographic fragment screening reveals ligand hotspots in TRIM21 PRY-SPRY domain Yeojin Kim , Aleksandar Lučić , Christopher Lenz , Frederic Farges , Martin P. Schwalm , Krishna Saxena , Thomas Hanke , Peter G. Marples , Jasmin C. Aschenbrenner , Daren Fearon , Frank Von Delft , Andreas Kramer , Stefan Knapp Communications Chemistry 8 DOI: 10.1038/s42004-025-01574-3 Diamond Proposal Number(s): [29658] Open Access Show Abstract ▼ Abstract: Tripartite motif-containing protein 21 (TRIM21), and particularly its PRY-SPRY protein interaction domain, plays a critical role in the immune response by recognizing intracellular antibodies targeting them for degradation. In this study, we performed a crystallographic fragment screening (CFS) campaign to identify potential small molecule binders targeting the PRY-SPRY domain of TRIM21. Our screen identified a total of 109 fragments binding to TRIM21 that were distributed across five distinct binding sites. These fragments have been designed to facilitate straightforward follow-up chemistry, making them ideal starting points for further chemical optimization. A subsequent fragment merging approach demonstrated improved activity. To enable functional validation of compounds with full length human TRIM21, we established a NanoBRET assay suitable for measuring target engagement to the main Fc binding site in life cells. The high-resolution structural data and observed binding modes across the different sites highlight the versatility of the PRY-SPRY domain as a target for small-molecule intervention. The presented data provide a solid foundation for structure-guided ligand design, enabling the rational design of more potent and selective compounds, with the goal to develop bivalent molecules such as Proteolysis Targeting Chimeras (PROTACs).	Jun 2025
	Where and how to house big data on small fragments Daniel A. Erlanson , Stephen Burley , Daren Fearon , James S. Fraser , Dale Kreitler , Maria Cristina Nonato , Naoki Sakai , Jan Wollenhaupt , Manfred S. Weiss Nature Communications 16 DOI: 10.1038/s41467-025-59233-z Open Access Show Abstract ▼ Abstract: ragment screening by crystallography has recently skyrocketed. Multiple synchrotrons have built specialized screening platforms, established workflows, and assembled compound libraries. Crystallographic fragment screening is now widely accessible to groups that had previously not considered the approach. While hundreds of crystallographic fragment-screening campaigns have been conducted in the last few years, most of the underlying data have neither been published nor made publicly accessible. This perspective highlights the importance of establishing effective mechanisms for preserving large and often heterogeneous groups of datasets intrinsic to crystallographic fragment-screening campaigns, thereby ensuring their accessibility for advancing research and enabling applications such as training AI-based models.	May 2025
I04-1-Macromolecular Crystallography (fixed wavelength)	Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets Martin P. Schwalm , Johannes Dopfer , Adarsh Kumar , Francesco A. Greco , Nicolas Bauer , Frank Löhr , Jan Heering , Sara Cano-Franco , Severin Lechner , Thomas Hanke , Ivana Jaser , Viktoria Morasch , Christopher Lenz , Daren Fearon , Peter G. Marples , Charles W. E. Tomlinson , Lorene Brunello , Krishna Saxena , Nathan B. P. Adams , Frank Von Delft , Susanne Müller , Alexandra Stolz , Ewgenij Proschak , Bernhard Kuster , Stefan Knapp , Vladimir V. Rogov Nature Communications 15 DOI: 10.1038/s41467-024-54409-5 Diamond Proposal Number(s): [29658] Open Access Show Abstract ▼ Abstract: Recent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the recruitment of targets to LC3/GABARAP, a family of ubiquitin-like proteins that presumably bind to the autophagosome membrane and tether cargo-loaded autophagy receptors into the autophagosome. In this work, we rigorously tested the target engagement of the reported ATTECs to validate the existing LC3/GABARAP ligands. Surprisingly, we were unable to detect interaction with their designated target LC3 using a diversity of biophysical methods. Intrigued by the idea of developing ATTECs, we evaluated the ligandability of LC3/GABARAP by in silico docking and large-scale crystallographic fragment screening. Data based on approximately 1000 crystal structures revealed that most fragments bound to the HP2 but not to the HP1 pocket within the LIR docking site, suggesting a favorable ligandability of HP2. Through this study, we identified diverse validated LC3/GABARAP ligands and fragments as starting points for chemical probe and ATTEC development.	Nov 2024
	Accelerating drug discovery with high-throughput crystallographic fragment screening and structural enablement Daren Fearon , Ailsa Powell , Alice Douangamath , Alexandre Dias , Charles W. E. Tomlinson , Blake H. Balcomb , Jasmin C. Aschenbrenner , Anthony Aimon , Isabel A. Barker , Jose Brandao-Neto , Patrick Collins , Louise E. Dunnett , Michael Fairhead , Richard J. Gildea , Mathew Golding , Tyler Gorrie-Stone , Paul V. Hathaway , Lizbe Koekemoer , Tobias Krojer , Ryan Lithgo , Elizabeth M. Maclean , Peter G. Marples , Xiaomin Ni , Rachael Skyner , Romain Talon , Warren Thompson , Conor F. Wild , Max Winokan , Nathan D. Wright , Graeme Winter , Elizabeth J. Shotton , Frank Von Delft Applied Research DOI: 10.1002/appl.202400192 Open Access Show Abstract ▼ Abstract: Fragment-based drug discovery is a well-established method for the identification of chemical starting points for development into clinical candidates. Historically, crystallographic fragment screening was perceived to be low-throughput and time consuming. However, thanks to advances in synchrotron capabilities and the introduction of dedicated facilities, such as the XChem platform at Diamond Light Source, there have been substantial improvements in throughput and integration between sample preparation, data collection and hit identification. Herein we share our experiences of establishing a crystallographic fragment screening facility, our learnings from operating a user programme for ten years and our perspective on applying structural enablement to rapidly progress initial fragment hits to lead-like molecules.	Nov 2024

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