Search Results

You searched for all publications:

with publication states 'Published (Approved)'

Search Again...

These results only include publications that have been reviewed and processed by Diamond Light Source. To also view papers that have not yet been processed click here.

You can use the folder icon under Actions to collate papers as required. You can then click on View Folder in the left-hand navigation to review and/or download your folder.

Exact matches
Related results

10 items found (0 items not approved), displaying all items.1

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	Application of an NMR/crystallography fragment screening platform for the assessment and rapid discovery of new HIV‐CA binding fragments Stuart Lang , Dan A. Fletcher , Alain-Pierre Petit , Nicola Luise , Paul K. Fyfe , Fabio Zuccotto , David Porter , Anthony Hope , Fiona Bellany , Catrina Kerr , Claire J. Mackenzie , Paul G. Wyatt , David W. Gray Chemmedchem DOI: 10.1002/cmdc.202400025 Diamond Proposal Number(s): [19844] Open Access Show Abstract ▼ Abstract: Identification and assessment of novel targets is essential to combat drug resistance in the treatment of HIV/AIDS. HIV Capsid (HIV-CA), the protein playing a major role in both the early and late stages of the viral life cycle, has emerged as an important target. We have applied an NMR fragment screening platform and identified molecules that bind to the N-terminal domain (NTD) of HIV-CA at a site close to the interface with the C-terminal domain (CTD). Using X-ray crystallography, we have been able to obtain crystal structures to identify the binding mode of these compounds. This allowed for rapid progression of the initial, weak binding, fragment starting points to compounds 37 and 38, which have 19F-pKi values of 5.3 and 5.4 respectively.	Apr 2024
I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	Identification and optimization of novel inhibitors of the polyketide synthase 13 thioesterase domain with antitubercular activity Simon R. Green , Caroline Wilson , Thomas C. Eadsforth , Avinash S. Punekar , Fabio K. Tamaki , Gavin Wood , Nicola Caldwell , Barbara Forte , Neil R. Norcross , Michael Kiczun , John M. Post , Eva Maria Lopez-Román , Curtis A. Engelhart , Iva Lukac , Fabio Zuccotto , Ola Epemolu , Helena I. M. Boshoff , Dirk Schnappinger , Chris Walpole , Ian H. Gilbert , Kevin D. Read , Paul G. Wyatt , Beatriz Baragaña Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.3c01514 Open Access Show Abstract ▼ Abstract: There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality of TB and to combat resistance to current treatments. Through both chemical and genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential for mycobacterial survival and as an attractive target for Mycobacterium tuberculosis growth inhibitors. A benzofuran series of inhibitors that targeted the Pks13 thioesterase domain, failed to progress to preclinical development due to concerns over cardiotoxicity. Herein, we report the identification of a novel oxadiazole series of Pks13 inhibitors, derived from a high-throughput screening hit and structure-guided optimization. This new series binds in the Pks13 thioesterase domain, with a distinct binding mode compared to the benzofuran series. Through iterative rounds of design, assisted by structural information, lead compounds were identified with improved antitubercular potencies (MIC < 1 μM) and in vitro ADMET profiles.	Nov 2023
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs Simon R. Green , Susan H. Davis , Sebastian Damerow , Curtis A. Engelhart , Michael Mathieson , Beatriz Baragaña , David A. Robinson , Jevgenia Tamjar , Alice Dawson , Fabio K. Tamaki , Kirsteen I. Buchanan , John Post , Karen Dowers , Sharon M. Shepherd , Chimed Jansen , Fabio Zuccotto , Ian H. Gilbert , Ola Epemolu , Jennifer Riley , Laste Stojanovski , Maria Osuna-Cabello , Esther Pérez-Herrán , María José Rebollo , Laura Guijarro López , Patricia Casado Castro , Isabel Camino , Heather C. Kim , James M. Bean , Navid Nahiyaan , Kyu Y. Rhee , Qinglan Wang , Vee Y. Tan , Helena I. M. Boshoff , Paul J. Converse , Si-Yang Li , Yong S. Chang , Nader Fotouhi , Anna M. Upton , Eric L. Nuermberger , Dirk Schnappinger , Kevin D. Read , Lourdes Encinas , Robert H. Bates , Paul G. Wyatt , Laura A. T. Cleghorn Nature Communications 13 DOI: 10.1038/s41467-022-33736-5 Diamond Proposal Number(s): [14980] Open Access Show Abstract ▼ Abstract: Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.	Oct 2022
I02-Macromolecular Crystallography I03-Macromolecular Crystallography	Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site Vitor Mendes , Simon R. Green , Joanna C. Evans , Jeannine Hess , Michael Blaszczyk , Christina Spry , Owain Bryant , James Cory-Wright , Daniel S-H. Chan , Pedro H. M. Torres , Zhe Wang , Navid Nahiyaan , Sandra O’neill , Sebastian Damerow , John Post , Tracy Bayliss , Sasha L. Lynch , Anthony G. Coyne , Peter C. Ray , Chris Abell , Kyu Y. Rhee , Helena I. M. Boshoff , Clifton E. Barry , Valerie Mizrahi , Paul G. Wyatt , Tom L. Blundell Nature Communications 12 DOI: 10.1038/s41467-020-20224-x Diamond Proposal Number(s): [9537, 14043, 18548] Open Access Show Abstract ▼ Abstract: Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB.	Jan 2021
I24-Microfocus Macromolecular Crystallography	Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis Beatriz Baragaña , Barbara Forte , Ryan Choi , Stephen Nakazawa Hewitt , Juan A. Bueren-Calabuig , Joao Pedro Pisco , Caroline Peet , David M. Dranow , David A. Robinson , Chimed Jansen , Neil R. Norcross , Sumiti Vinayak , Mark Anderson , Carrie F. Brooks , Caitlin A. Cooper , Sebastian Damerow , Michael Delves , Karen Dowers , James Duffy , Thomas E. Edwards , Irene Hallyburton , Benjamin G. Horst , Matthew A. Hulverson , Liam Ferguson , María Belén Jiménez-Díaz , Rajiv S. Jumani , Donald D. Lorimer , Melissa S. Love , Steven Maher , Holly Matthews , Case W. Mcnamara , Peter Miller , Sandra O’neill , Kayode K. Ojo , Maria Osuna-Cabello , Erika Pinto , John Post , Jennifer Riley , Matthias Rottmann , Laura M. Sanz , Paul Scullion , Arvind Sharma , Sharon M. Shepherd , Yoko Shishikura , Frederick R. C. Simeons , Erin E. Stebbins , Laste Stojanovski , Ursula Straschil , Fabio K. Tamaki , Jevgenia Tamjar , Leah S. Torrie , Amélie Vantaux , Benoît Witkowski , Sergio Wittlin , Manickam Yogavel , Fabio Zuccotto , Iñigo Angulo-Barturen , Robert Sinden , Jake Baum , Francisco-Javier Gamo , Pascal Mäser , Dennis E. Kyle , Elizabeth A. Winzeler , Peter J. Myler , Paul G. Wyatt , David Floyd , David Matthews , Amit Sharma , Boris Striepen , Christopher D. Huston , David W. Gray , Alan H. Fairlamb , Andrei V. Pisliakov , Chris Walpole , Kevin D. Read , Wesley C. Van Voorhis , Ian H. Gilbert Proceedings Of The National Academy Of Sciences 116, 7015 - 7020 DOI: 10.1073/pnas.1814685116 Diamond Proposal Number(s): [10071] Open Access Show Abstract ▼ Abstract: Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.	Apr 2019
I03-Macromolecular Crystallography	A molecular hybridization approach for the design of potent, highly selective, and brain-penetrant n-myristoyltransferase inhibitors Justin R. Harrison , Stephen Brand , Victoria Smith , David A. Robinson , Stephen Thompson , Alasdair Smith , Kenneth Davies , Ngai Mok , Leah S. Torrie , Iain Collie , Irene Hallyburton , Suzanne Norval , Frederick R. C. Simeons , Laste Stojanovski , Julie A. Frearson , Ruth Brenk , Paul G. Wyatt , Ian H. Gilbert , Kevin D. Read Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00884 Diamond Proposal Number(s): [7705] Open Access Show Abstract ▼ Abstract: Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood–brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.	Sep 2018
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Screening of a novel fragment library with functional complexity against Mycobacterium tuberculosis InhA Federica Prati , Fabio Zuccotto , Daniel Fletcher , Maire A. Convery , Raquel Fernandez-Menendez , Robert Bates , Lourdes Encinas , Jingkun Zeng , Chun-Wa Chung , Paco De Dios Anton , Alfonso Mendoza-Losana , Claire Mackenzie , Simon R. Green , Margaret Huggett , David Barros , Paul G. Wyatt , Peter C. Ray Chemmedchem DOI: 10.1002/cmdc.201700774 Diamond Proposal Number(s): [12279] Open Access Show Abstract ▼ Abstract: Our findings reported herein, provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.	Feb 2018
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Essential but not vulnerable: indazole sulfonamides targeting inosine monophosphate dehydrogenase as potential leads against Mycobacterium tuberculosis Yumi Park , Angela Pacitto , Tracy Bayliss , Laura A. T. Cleghorn , Zhe Wang , Travis Hartman , Kriti Arora , Thomas R. Ioerger , Jim Sacchettini , Menico Rizzi , Stefano Donini , Tom L. Blundell , David B. Ascher , Kyu Rhee , Ardala Breda , Nian Zhou , Veronique Dartois , Surendranadha Reddy Jonnala , Laura E. Via , Valerie Mizrahi , Ola Epemolu , Laste Stojanovski , Fred Simeons , Maria Osuna-Cabello , Lucy Ellis , Claire J. Mackenzie , Alasdair R. C. Smith , Susan H. Davis , Dinakaran Murugesan , Kirsteen I. Buchanan , Penelope A. Turner , Margaret Huggett , Fabio Zuccotto , Maria Jose Rebollo-Lopez , Maria Jose Lafuente-Monasterio , Olalla Sanz , Gracia Santos Diaz , Joël Lelièvre , Lluis Ballell , Carolyn Selenski , Matthew Axtman , Sonja Ghidelli-Disse , Hannah Pflaumer , Markus Bösche , Gerard Drewes , Gail M. Freiberg , Matthew D. Kurnick , Myron Srikumaran , Dale J. Kempf , Simon R. Green , Peter C. Ray , Kevin Read , Paul Wyatt , Clifton E. Barry , Helena I. Boshoff Acs Infectious Diseases DOI: 10.1021/acsinfecdis.6b00103 Diamond Proposal Number(s): [9537] Show Abstract ▼ Abstract: A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH–IMP–inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi–pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time–kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5–2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.	Oct 2016
I03-Macromolecular Crystallography	Development of small-molecule Trypanosoma brucei n-myristoyltransferase inhibitors: discovery and optimisation of a novel binding mode Daniel Spinks , Victoria Smith , Stephen Thompson , David Robinson , Torsten Luksch , Alasdair Smith , Leah S. Torrie , Stuart Mcelroy , Laste Stojanovski , Suzanne Norval , Iain T. Collie , Irene Hallyburton , Bhavya Rao , Stephen Brand , Ruth Brenk , Julie A. Frearson , Kevin D. Read , Paul G. Wyatt , Ian H. Gilbert Chemmedchem 10, 1821 - 1836 DOI: 10.1002/cmdc.201500301 PMID: 26395087 Open Access Show Abstract ▼ Abstract: The enzyme N-myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high-throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. An X-ray crystal structure of the thiazolidinone hit in Leishmania major NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X-ray crystallography/structure-based design approach, the benzomorpholinone series was further optimised, increasing activity against T. brucei NMT by >1000-fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against T. brucei.	Nov 2015
I04-1-Macromolecular Crystallography (fixed wavelength)	Identification and structure solution of fragment hits against kinetoplastid N-myristoyltransferase David A Robinson , Paul G. Wyatt Acta Crystallographica Section F Structural Biology Communications 71 (5), 586 - 593 DOI: 10.1107/S2053230X15003040 PMID: 25945713 Open Access Show Abstract ▼ Abstract: Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis. Pyrazole sulfonamide (DDD85646), a potent inhibitor of TbNMT, has been identified in previous studies; however, poor central nervous system exposure restricts its use to the haemolymphatic form (stage 1) of the disease. In order to identify new chemical matter, a fragment screen was carried out by ligand-observed NMR spectroscopy, identifying hits that occupy the DDD85646 binding site. Crystal structures of hits from this assay have been obtained in complex with the closely related NMT from Leishmania major, providing a structural starting point for the evolution of novel chemical matter.	May 2015

Publications Database

Search Results

You searched for all publications:

Search Again...

Subject Areas (check all that apply) select all

Instruments used to collect data (check all that apply) select all

Collaborations involved (check all that apply) select all

Diamond Offline Facilities used

Relevant Technical Areas (check all that apply) select all

Menu for Anonymous User