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

Instruments / Technical Area	Publication Details	Published
	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
I04-1-Macromolecular Crystallography (fixed wavelength)	SAMPL7 protein-ligand challenge: A community-wide evaluation of computational methods against fragment screening and pose-prediction Harold Grosjean , Mehtap Işık , Anthony Aimon , David Mobley , John Chodera , Frank Von Delft , Philip C. Biggin Journal Of Computer-Aided Molecular Design 14 DOI: 10.1007/s10822-022-00452-7 Diamond Proposal Number(s): [18145] Open Access Show Abstract ▼ Abstract: A novel crystallographic fragment screening data set was generated and used in the SAMPL7 challenge for protein-ligands. The SAMPL challenges prospectively assess the predictive power of methods involved in computer-aided drug design. Application of various methods to fragment molecules are now widely used in the search for new drugs. However, there is little in the way of systematic validation specifically for fragment-based approaches. We have performed a large crystallographic high-throughput fragment screen against the therapeutically relevant second bromodomain of the Pleckstrin-homology domain interacting protein (PHIP2) that revealed 52 different fragments bound across 4 distinct sites, 47 of which were bound to the pharmacologically relevant acetylated lysine (Kac) binding site. These data were used to assess computational screening, binding pose prediction and follow-up enumeration. All submissions performed randomly for screening. Pose prediction success rates (defined as less than 2 Å root mean squared deviation against heavy atom crystal positions) ranged between 0 and 25% and only a very few follow-up compounds were deemed viable candidates from a medicinal-chemistry perspective based on a common molecular descriptors analysis. The tight deadlines imposed during the challenge led to a small number of submissions suggesting that the accuracy of rapidly responsive workflows remains limited. In addition, the application of these methods to reproduce crystallographic fragment data still appears to be very challenging. The results show that there is room for improvement in the development of computational tools particularly when applied to fragment-based drug design.	Apr 2022
I03-Macromolecular Crystallography	Expanding the repertoire of low-molecular-weight pentafluorosulfanyl-substituted scaffolds Arathy Jose , Daniel Guest , Remi Legay , Graham J. Tizzard , Simon Coles , Mariliza Derveni , Edward Wright , Lester Marrison , Alpha A. Lee , Aaron Morris , Matt Robinson , Frank Von Delft , Daren Fearon , Lizbe Koekemoer , Tetiana Matviuk , Anthony Aimon , Christopher J. Schofield , Tika R. Malla , Nir London , Barnaby W. Greenland , Mark C. Bagley , John Spencer Chemmedchem 59 DOI: 10.1002/cmdc.202100641 Diamond Proposal Number(s): [19301] Open Access Show Abstract ▼ Abstract: The pentafluorosulfanyl (-SF5) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF5-containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solution-based and solventless methods, including microwave and ball-mill techniques. The library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subsequent focused approach led to synthesis of analogues of the clinically used disease modifying anti-rheumatic drugs (DMARDs), Teriflunomide and Leflunomide, considered for potential COVID-19 use, where SF5 bioisostere deployment led to improved inhibition of HDHODH compared with the parent drugs. The results demonstrate the utility of the SF5 group in medicinal chemistry.	Feb 2022
I04-1-Macromolecular Crystallography (fixed wavelength)	Structure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase Joseph A. Newman , Alice Douangamath , Setayesh Yadzani , Yuliana Yosaatmadja , Anthony Aimon , Jose Brandao-Neto , Louise Dunnett , Tyler Gorrie-Stone , Rachael Skyner , Daren Fearon , Matthieu Schapira , Frank Von Delft , Opher Gileadi Nature Communications 12 DOI: 10.1038/s41467-021-25166-6 Diamond Proposal Number(s): [26998] Open Access Show Abstract ▼ Abstract: There is currently a lack of effective drugs to treat people infected with SARS-CoV-2, the cause of the global COVID-19 pandemic. The SARS-CoV-2 Non-structural protein 13 (NSP13) has been identified as a target for anti-virals due to its high sequence conservation and essential role in viral replication. Structural analysis reveals two “druggable” pockets on NSP13 that are among the most conserved sites in the entire SARS-CoV-2 proteome. Here we present crystal structures of SARS-CoV-2 NSP13 solved in the APO form and in the presence of both phosphate and a non-hydrolysable ATP analog. Comparisons of these structures reveal details of conformational changes that provide insights into the helicase mechanism and possible modes of inhibition. To identify starting points for drug development we have performed a crystallographic fragment screen against NSP13. The screen reveals 65 fragment hits across 52 datasets opening the way to structure guided development of novel antiviral agents.	Aug 2021
NONE-No attached Diamond beamline	Achieving efficient fragment screening at XChem facility at Diamond Light Source Alice Douangamath , Alisa Powell , Daren Fearon , Patrick M. Collins , Romain Talon , Tobias Krojer , Rachael Skyner , Jose Brandao-Neto , Louise Dunnett , Alexandre Dias , Anthony Aimon , Nicholas M. Pearce , Conor Wild , Tyler J. Gorrie-Stone , Frank Von Delft Journal Of Visualized Experiments DOI: 10.3791/62414 Open Access Show Abstract ▼ Abstract: In fragment-based drug discovery, hundreds or often thousands of compounds smaller than ~300 Da are tested against the protein of interest to identify chemical entities that can be developed into potent drug candidates. Since the compounds are small, interactions are weak, and the screening method must therefore be highly sensitive; moreover, structural information tends to be crucial for elaborating these hits into lead-like compounds. Therefore, protein crystallography has always been a gold-standard technique, yet historically too challenging to find widespread use as a primary screen. Initial XChem experiments were demonstrated in 2014 and then trialed with academic and industrial collaborators to validate the process. Since then, a large research effort and significant beamtime have streamlined sample preparation, developed a fragment library with rapid follow-up possibilities, automated and improved the capability of I04-1 beamline for unattended data collection, and implemented new tools for data management, analysis and hit identification. XChem is now a facility for large-scale crystallographic fragment screening, supporting the entire crystals-to-deposition process, and accessible to academic and industrial users worldwide. The peer-reviewed academic user program has been actively developed since 2016, to accommodate projects from as broad a scientific scope as possible, including well-validated as well as exploratory projects. Academic access is allocated through biannual calls for peer-reviewed proposals, and proprietary work is arranged by Diamond's Industrial Liaison group. This workflow has already been routinely applied to over a hundred targets from diverse therapeutic areas, and effectively identifies weak binders (1%-30% hit rate), which both serve as high-quality starting points for compound design and provide extensive structural information on binding sites. The resilience of the process was demonstrated by continued screening of SARS-CoV-2 targets during the COVID-19 pandemic, including a 3-week turn-around for the main protease.	May 2021
I04-1-Macromolecular Crystallography (fixed wavelength)	Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking Marion Schuller , Galen J. Correy , Stefan Gahbauer , Daren Fearon , Taiasean Wu , Roberto Efraín Díaz , Iris D. Young , Luan Carvalho Martins , Dominique H. Smith , Ursula Schulze-Gahmen , Tristan W. Owens , Ishan Deshpande , Gregory E. Merz , Aye C. Thwin , Justin T. Biel , Jessica K. Peters , Michelle Moritz , Nadia Herrera , Huong T. Kratochvil , Anthony Aimon , James Bennett , Jose Brandao Neto , Aina E. Cohen , Alexandre Dias , Alice Douangamath , Louise Dunnett , Oleg Fedorov , Matteo P. Ferla , Martin R. Fuchs , Tyler J. Gorrie-Stone , James M. Holton , Michael G. Johnson , Tobias Krojer , George Meigs , Alisa J. Powell , Johannes Gregor Matthias Rack , Victor Rangel , Silvia Russi , Rachael E. Skyner , Clyde A. Smith , Alexei S. Soares , Jennifer L. Wierman , Kang Zhu , Peter O’brien , Natalia Jura , Alan Ashworth , John J. Irwin , Michael C. Thompson , Jason E. Gestwicki , Frank Von Delft , Brian K. Shoichet , James S. Fraser , Ivan Ahel Science Advances 7 DOI: 10.1126/sciadv.abf8711 Diamond Proposal Number(s): [27001] Open Access Show Abstract ▼ Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate–ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.	Apr 2021
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease Alice Douangamath , Daren Fearon , Paul Gehrtz , Tobias Krojer , Petra Lukacik , C. David Owen , Efrat Resnick , Claire Strain-Damerell , Anthony Aimon , Péter Ábrányi-Balogh , Jose Brandao-Neto , Anna Carbery , Gemma Davison , Alexandre Dias , Thomas D. Downes , Louise Dunnett , Michael Fairhead , James D. Firth , S. Paul Jones , Aaron Keeley , György M. Keserü , Hanna F. Klein , Mathew P. Martin , Martin M. Noble , Peter O’brien , Ailsa Powell , Rambabu N. Reddi , Rachael Skyner , Matthew Snee , Michael J. Waring , Conor Wild , Nir London , Frank Von Delft , Martin A. Walsh Nature Communications 11 DOI: 10.1038/s41467-020-18709-w Open Access Show Abstract ▼ Abstract: COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.	Oct 2020
I04-1-Macromolecular Crystallography (fixed wavelength)	Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures Lisa M. Baker , Anthony Aimon , James B. Murray , Allan E. Surgenor , Natalia Matassova , Stephen D. Roughley , Patrick M. Collins , Tobias Krojer , Frank Von Delft , Roderick E. Hubbard Communications Chemistry 3 DOI: 10.1038/s42004-020-00367-0 Open Access Show Abstract ▼ Abstract: Fragment based methods are now widely used to identify starting points in drug discovery and generation of tools for chemical biology. A significant challenge is optimization of these weak binding fragments to hit and lead compounds. We have developed an approach where individual reaction mixtures of analogues of hits can be evaluated without purification of the product. Here, we describe experiments to optimise the processes and then assess such mixtures in the high throughput crystal structure determination facility, XChem. Diffraction data for crystals of the proteins Hsp90 and PDHK2 soaked individually with 83 crude reaction mixtures are analysed manually or with the automated XChem procedures. The results of structural analysis are compared with binding measurements from other biophysical techniques. This approach can transform early hit to lead optimisation and the lessons learnt from this study provide a protocol that can be used by the community.	Sep 2020
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion Sarah L. Kidd , Elaine Fowler , Till Reinhardt , Thomas Compton , Natalia Mateu , Hector Newman , Dom Bellini , Romain Talon , Joseph Mcloughlin , Tobias Krojer , Anthony Aimon , Anthony Bradley , Michael Fairhead , Paul Brear , Laura Diaz-Saez , Katherine Mcauley , Hannah F. Sore , Andrew Madin , Daniel H. O'Donovan , Kilian Huber , Marko Hyvonen , Frank Von Delft , Christopher G. Dowson , David R. Spring Chemical Science DOI: 10.1039/D0SC01232G Diamond Proposal Number(s): [18145, 15649, 14303, 14493] Open Access Show Abstract ▼ Abstract: Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10–14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery.	May 2020
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Rapid covalent-probe discovery by electrophile-fragment screening Efrat Resnick , Anthony Bradley , Jinrui Gan , Alice Douangamath , Tobias Krojer , Ritika Sethi , Paul P. Geurink , Anthony Aimon , Gabriel Amitai , Dom Bellini , James Bennett , Michael Fairhead , Oleg Fedorov , Ronen Gabizon , Jin Gan , Jingxu Guo , Alexander Plotnikov , Nava Reznik , Gian Filippo Ruda , Laura Diaz-Saez , Verena M. Straub , Tamas Szommer , Srikannathasan Velupillai , Daniel Zaidman , Yanling Zhang , Alun R. Coker , Christopher G. Dowson , Haim Barr , Chu Wang , Kilian V. M. Huber , Paul E. Brennan , Huib Ovaa , Frank Von Delft , Nir London Journal Of The American Chemical Society DOI: 10.1021/jacs.9b02822 Show Abstract ▼ Abstract: Covalent probes can display unmatched potency, selectivity and duration of action; however, their discovery is challenging. In principle, fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening, but such electrophilic fragments were considered non-selective and were rarely screened. We hypothesized that mild electrophiles might overcome the selectivity challenge and constructed a library of 993 mildly electrophilic fragments. We characterized this library by a new high-throughput thiol-reactivity assay and screened them against ten cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. By contrast, we found hits for most targets. Combining our approach with high-throughput crystallography allowed rapid progression to potent and selective probes for two enzymes, the deubiquitinase OTUB2 and the pyrophosphatase NUDT7. No inhibitors were previously known for either. This study highlights the potential of electrophile-fragment screening as a practical and efficient tool for covalent-ligand discovery.	May 2019

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