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

Instruments / Technical Area	Publication Details	Published
	Ugi-tetrazole-derived α-aminomethyl scaffolds reveal unexpected binding modes in SARS-CoV-2 3CLpro Robin Van Der Straat , Rick Oerlemans , Yingying Cong , Jeffrey Boxma , Radu G. Bulai , Clàudia Río-Bergé , Lizbe Koekemoer , Tryfon Zarganes Tzitzikas , Zhirui Guan , Peter G. Marples , Fulvio Reggiori , Matthew Groves , Alexander Dömling Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.5c00773 Open Access Show Abstract ▼ Abstract: The SARS-CoV-2 main protease (3CLpro) is a well-validated target for structure-guided inhibitor discovery. Here, we report α-aminomethyl tetrazole inhibitors accessed via the Ugi tetrazole multicomponent reaction (UT-4CR), enabling rapid exploration of non-classical chemical space. Initial design and modeling suggested a binding mode analogous to Ugi-derived (U-4CR) 3CLpro inhibitors, with heteroaromatic substituents engaging the S1 pocket. However, crystallographic analysis revealed an unexpected binding orientation in which the tetrazole core itself occupies the S1 pocket and forms the key interaction with His163, while the modeled substituents are solvent-exposed. This revised binding mode rationalizes the observed structure–activity relationships. Installation of an electrophilic warhead yielded covalent inhibitors with sub-micromolar enzymatic potency, and lead compound 2a displayed modest antiviral activity in infected cells. These results highlight UT-4CR-derived tetrazoles as a platform for probing the 3CLpro binding space and underscore the importance of early crystallographic validation.	Mar 2026
I03-Macromolecular Crystallography	High-affinity peptide-drug conjugate ligands for the TRIM24 PHD and bromodomain Michael A. Platt , Ekaterina Kot , Louise A. W. Martin , Antoine L. D. Wallabrègue , Liwen Song , Alistair M. Boyd , Lizbe Koekemoer , Ester M. Hammond , Stuart J. Conway Chemistry - A European Journal DOI: 10.1002/chem.202503011 Open Access Show Abstract ▼ Abstract: TRIM24 is an epigenetic transcriptional coregulator that “reads” KMe3 and KAc histone modifications via its tandem plant homeodomain (PHD) and bromodomain (BRD), respectively. The PHD and BRD are potential therapeutic targets due to the roles of TRIM24 in breast cancer progression. However, there are currently no small-molecule ligands for the PHD, and existing TRIM24 BRD inhibitors lack selectivity over the main off-target, BRPF1. Here, we report the development of the first bivalent tool molecules capable of simultaneously engaging both the TRIM24 PHD and BRD. Key to this strategy was the identification of effective KMe3 bioisosteres that enhance H3 peptide binding to the TRIM24 PHD. The most promising of these was incorporated into a nine amino acid H3-mimicking peptide, and linked to a TRIM24 BRD ligand. The resulting peptide-drug conjugates (PDCs) bind to TRIM24 with picomolar affinity and a slow dissociation rate (koff), which is driven by an in cis bivalent binding mode. Although the PDCs showed limited effects on breast cancer cell proliferation in vitro, this work underscores their potential as tools for studying previously unliganded reader domains and consequently advancing our understanding of multivalent epigenetic regulation in disease.	Nov 2025
I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	Gluebodies offer a route to improve crystal reliability and diversity through transferable nanobody mutations that introduce constitutive close contacts Mingda Ye , Mpho Makola , Mark W. Richards , Joseph A. Newman , Michael Fairhead , Selena G. Burgess , Zhihuang Wu , Elizabeth Maclean , Nathan D. Wright , Lizbe Koekemoer , Andrew Thompson , Gustavo Arruda Bezerra , Gangshun Yi , Huanyu Li , Victor Rangel , Dimitrios Mamalis , Hazel Aitkenhead , Benjamin G. Davis , Robert J. C. Gilbert , Katharina L. Duerr , Richard Bayliss , Opher Gileadi , Frank Von Delft Acs Central Science DOI: 10.1021/acscentsci.5c00937 Diamond Proposal Number(s): [26998] Open Access Show Abstract ▼ Abstract: Design of modular, transferable protein assemblies has broad applicability and in structural biology could help with the ever-troublesome crystallization bottleneck, including finding robustly behaved protein crystals for rapidly characterizing ligands or drug candidates or generating multiple polymorphs to illuminate diverse conformations. Nanobodies as crystallization chaperones are well-established but still unreliable, as we show here. Instead, we show an exemplar of how robust crystallization behavior can be engineered by exploring many combinations (>200) of nanobody surface mutations over several iterations. Critically, what needed testing was crystallization and diffraction quality, since target–nanobody binding affinity is decoupled from crystallizability enhancement. Our study yielded multiple polymorphs, all mediated by the same interface, with dramatically improved resolution and diffraction reliability for some mutants; we thus name them ‘Gluebodies’ (Gbs). We further demonstrate that these Gb mutations do transfer to some other targets, both for achieving robust crystallization in alternative packing forms and for establishing the ability to crystallize a key early stage readout. Since the Gb interface is evidently a favored interaction, it may be broadly applicable for modular assembly; more specifically, this work suggests that Gbs should be routinely attempted for crystallization whenever nanobodies are available.	Oct 2025
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
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
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Binding‐site purification of actives (B‐SPA) enables efficient large‐scale progression of fragment hits by combining multi‐step array synthesis with HT crystallography Harold Grosjean , Anthony Aimon , Storm Hassell-Hart , Warren Thompson , Lizbe Koekemoer , James Bennett , Anthony Bradley , Cameron Anderson , Conor Wild , William J. Bradshaw , Edward A. Fitzgerald , Tobias Krojer , Oleg Fedorov , Philip C. Biggin , John Spencer , Frank Von Delft Angewandte Chemie International Edition DOI: 10.1002/anie.202424373 Diamond Proposal Number(s): [19301] Show Abstract ▼ Abstract: Fragment approaches are long-established in target-based ligand discovery yet their full transformative potential lies dormant, because progressing hits to potency remains underserved by methodological work. The only credible progression paradigm is multiple cycles of costly conventional design-make-test-analyse (DMTA) medicinal chemistry, necessitating picking winners early and discarding others. It is effective to cheaply parallelize large numbers of non-uniform multi-step reactions, because, even without compound purification, a high-quality readout of binding is available, viz. crystallography. This can detect low-level binding of slightly active compounds, which the targeted binding site extracts directly from crude reaction mixtures (CRMs). In this proof-of-concept study, we expand a fragment hit from a crystal-based screen of the bromodomain PHIP2, using array synthesis on low-cost robotics to implement 6 independent multi-step reaction routes of up to 5 steps, attempting the synthesis of 1876 diverse expansions, designs entirely driven by synthetic tractability. The expected product was present in 1108 (59%) CRMs, detected by automated mass spectrometry, 22 individual products were resolved in crystal structures of CRMs added to crystals, providing an initial SAR map, pose stability in 19 and instability in 3 products and resolved stereochemical preference. One compound showed biochemical potency (IC50=34 μM) and affinity (Kd=50 μM) after resynthesis.	Feb 2025
	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
I03-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Analysis of the diverse antigenic landscape of the malaria protein RH5 identifies a potent vaccine-induced human public antibody clonotype Jordan R. Barrett , Dimitra Pipini , Nathan D. Wright , Andrew J. R. Cooper , Giacomo Gorini , Doris Quinkert , Amelia M. Lias , Hannah Davies , Cassandra A. Rigby , Maya Aleshnick , Barnabas G. Williams , William J. Bradshaw , Neil G. Paterson , Thomas Martinson , Payton Kirtley , Luc Picard , Christine D. Wiggins , Francesca R. Donnellan , Lloyd D. W. King , Lawrence T. Wang , Jonathan F. Popplewell , Sarah E. Silk , Jed De Ruiter Swain , Katherine Skinner , Vinayaka Kotraiah , Amy R. Noe , Randall S. Macgill , C. Richter King , Ashley J. Birkett , Lorraine A. Soisson , Angela M. Minassian , Douglas A. Lauffenburger , Kazutoyo Miura , Carole A. Long , Brandon K. Wilder , Lizbe Koekemoer , Joshua Tan , Carolyn M. Nielsen , Kirsty Mchugh , Simon J. Draper Cell 24 DOI: 10.1016/j.cell.2024.06.015 Diamond Proposal Number(s): [28172] Open Access Show Abstract ▼ Abstract: The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.	Jul 2024
I04-1-Macromolecular Crystallography (fixed wavelength)	Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors Melissa L. Boby , Daren Fearon , Matteo Ferla , Mihajlo Filep , Lizbe Koekemoer , Matthew C. Robinson , The Covid Moonshot Consortium , John D. Chodera , Alpha A. Lee , Nir London , Annette Von Delft , Frank Von Delft Science 382 DOI: 10.1126/science.abo7201 Show Abstract ▼ Abstract: We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property–free knowledge base for future anticoronavirus drug discovery.	Nov 2023
Krios II-Titan Krios II at Diamond	An in-solution snapshot of SARS-COV-2 main protease maturation process and inhibition Gabriela Dias Noske , Yun Song , Rafaela Sachetto Fernandes , Rod Chalk , Haitem Elmassoudi , Lizbe Koekemoer , C. David Owen , Tarick J. El-Baba , Carol V. Robinson , Glaucius Oliva , Andre Schutzer Godoy Nature Communications 14 DOI: 10.1038/s41467-023-37035-5 Diamond Proposal Number(s): [27083, 29349] Open Access Show Abstract ▼ Abstract: The main protease from SARS-CoV-2 (Mpro) is responsible for cleavage of the viral polyprotein. Mpro self-processing is called maturation, and it is crucial for enzyme dimerization and activity. Here we use C145S Mpro to study the structure and dynamics of N-terminal cleavage in solution. Native mass spectroscopy analysis shows that mixed oligomeric states are composed of cleaved and uncleaved particles, indicating that N-terminal processing is not critical for dimerization. A 3.5 Å cryo-EM structure provides details of Mpro N-terminal cleavage outside the constrains of crystal environment. We show that different classes of inhibitors shift the balance between oligomeric states. While non-covalent inhibitor MAT-POS-e194df51-1 prevents dimerization, the covalent inhibitor nirmatrelvir induces the conversion of monomers into dimers, even with intact N-termini. Our data indicates that the Mpro dimerization is triggered by induced fit due to covalent linkage during substrate processing rather than the N-terminal processing.	Mar 2023

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