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

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	A new strategy for hit generation: Novel in cellulo active inhibitors of CYP121A1 from Mycobacterium tuberculosis via a combined X-ray crystallographic and phenotypic screening approach (XP screen) Martyn Frederickson , Irwin R. Selvam , Dimitrios Evangelopoulos , Kirsty J. Mclean , Mona M. Katariya , Richard B. Tunnicliffe , Bethany Campbell , Madeline E. Kavanagh , Sitthivut Charoensutthivarakul , Richard T. Blankley , Colin W. Levy , Luiz Pedro S. De Carvalho , David Leys , Andrew W. Munro , Anthony G. Coyne , Chris Abell European Journal Of Medicinal Chemistry 393 DOI: 10.1016/j.ejmech.2022.114105 Diamond Proposal Number(s): [17773, 24447] Open Access Show Abstract ▼ Abstract: There is a pressing need for new drugs against tuberculosis (TB) to combat the growing resistance to current antituberculars. Herein a novel strategy is described for hit generation against promising TB targets involving X-ray crystallographic screening in combination with phenotypic screening. This combined approach (XP Screen) affords both a validation of target engagement as well as determination of in cellulo activity. The utility of this method is illustrated by way of an XP Screen against CYP121A1, a cytochrome P450 enzyme from Mycobacterium tuberculosis (Mtb) championed as a validated drug discovery target. A focused screening set was synthesized and tested by such means, with several members of the set showing promising activity against Mtb strain H37Rv. One compound was observed as an X-ray hit against CYP121A1 and showed improved activity against Mtb strain H37Rv under multiple assay conditions (pan-assay activity). Data obtained during X-ray crystallographic screening were utilized in a structure-based campaign to design a limited number of analogues (less than twenty), many of which also showed pan-assay activity against Mtb strain H37Rv. These included the benzo[b][1,4]oxazine derivative (MIC90 6.25 μM), a novel hit compound suitable as a starting point for a more involved lead-to-clinical candidate medicinal chemistry campaign.	Jan 2022
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Development of inhibitors of SAICAR synthetase (PurC) from Mycobacterium abscessus using a fragment-based approach Sitthivut Charoensutthivarakul , Sherine E. Thomas , Amy Curran , Karen P. Brown , Juan M. Belardinelli , Andrew J. Whitehouse , Marta Acebron-Garcia-De-Eulate , Jaspar Sangan , Subramanian G. Gramani , Mary Jackson , Vitor Mendes , R. Andres Floto , Tom L. Blundell , Anthony G. Coyne , Chris Abell Acs Infectious Diseases DOI: 10.1021/acsinfecdis.1c00432 Diamond Proposal Number(s): [9537, 14043, 18548] Show Abstract ▼ Abstract: Mycobacterium abscessus (Mab) has emerged as a challenging threat to individuals with cystic fibrosis. Infections caused by this pathogen are often impossible to treat due to the intrinsic antibiotic resistance leading to lung malfunction and eventually death. Therefore, there is an urgent need to develop new drugs against novel targets in Mab to overcome drug resistance and subsequent treatment failure. In this study, SAICAR synthetase (PurC) from Mab was identified as a promising target for novel antibiotics. An in-house fragment library screen and a high-throughput X-ray crystallographic screen of diverse fragment libraries were explored to provide crucial starting points for fragment elaboration. A series of compounds developed from fragment growing and merging strategies, guided by crystallographic information and careful hit-to-lead optimization, have achieved potent nanomolar binding affinity against the enzyme. Some compounds also show a promising inhibitory effect against Mab and Mtb. This work utilizes a fragment-based design and demonstrates for the first time the potential to develop inhibitors against PurC from Mab.	Jan 2022
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Discovery of novel inhibitors of uridine diphosphate-n-acetylenolpyruvylglucosamine reductase (MurB) from Pseudomonas aeruginosa, an opportunistic infectious agent causing death in cystic fibrosis patients Marta Acebron-Garcia-De-Eulate , Joan Mayol-Llinàs , Matthew T. O. Holland , So Yeon Kim , Karen P. Brown , Chiara Marchetti , Jeannine Hess , Ornella Di Pietro , Vitor Mendes , Chris Abell , R. Andres Floto , Anthony G. Coyne , Tom L. Blundell Journal Of Medicinal Chemistry 48 DOI: 10.1021/acs.jmedchem.1c01684 Diamond Proposal Number(s): [18548] Show Abstract ▼ Abstract: Pseudomonas aeruginosa is of major concern for cystic fibrosis patients where this infection can be fatal. With the emergence of drug-resistant strains, there is an urgent need to develop novel antibiotics against P. aeruginosa. MurB is a promising target for novel antibiotic development as it is involved in the cell wall biosynthesis. MurB has been shown to be essential in P. aeruginosa, and importantly, no MurB homologue exists in eukaryotic cells. A fragment-based drug discovery approach was used to target Pa MurB. This led to the identification of a number of fragments, which were shown to bind to MurB. One fragment, a phenylpyrazole scaffold, was shown by ITC to bind with an affinity of Kd = 2.88 mM (LE 0.23). Using a structure guided approach, different substitutions were synthesized and the initial fragment was optimized to obtain a small molecule with Kd = 3.57 μM (LE 0.35).	Jan 2022
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis Pooja Gupta , Sherine E. Thomas , Shaymaa A. Zaidan , Maria A. Pasillas , James Cory-Wright , Víctor Sebastián-Pérez , Ailidh Burgess , Emma Cattermole , Clio Meghir , Chris Abell , Anthony G. Coyne , William R. Jacobs , Tom L. Blundell , Sangeeta Tiwari , Vitor Mendes Computational And Structural Biotechnology Journal 19, 3491 - 3506 DOI: 10.1016/j.csbj.2021.06.006 Diamond Proposal Number(s): [14043, 18548] Open Access Show Abstract ▼ Abstract: The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) of Mycobacterium tuberculosis are rapidly sterilised in mice, while inhibition of ArgJ with Pranlukast was found to clear chronic M. tuberculosis infection in a mouse model. Enzymes in the arginine biosynthetic pathway have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is assessed using a fragment-based approach. We identify several hits against these enzymes validated with biochemical and biophysical assays, as well as X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity against M. tuberculosis. These results demonstrate the potential for more enzymes in this pathway to be targeted with dedicated drug discovery programmes.	Jun 2021
I02-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death Duncan E. Scott , Nicola J. Francis-Newton , May E. Marsh , Anthony G. Coyne , Gerhard Fischer , Tommaso Moschetti , Andrew R. Bayly , Timothy D. Sharpe , Kalina T. Haas , Lorraine Barber , Chiara R. Valenzano , Rajavel Srinivasan , David J. Huggins , Miyoung Lee , Amy Emery , Bryn Hardwick , Matthias Ehebauer , Claudio Dagostin , Alessandro Esposito , Luca Pellegrini , Trevor Perrior , Grahame Mckenzie , Tom L. Blundell , Marko Hyvonen , John Skidmore , Ashok R. Venkitaraman , Chris Abell Cell Chemical Biology 66 DOI: 10.1016/j.chembiol.2021.02.006 Diamond Proposal Number(s): [315, 7141] Open Access Show Abstract ▼ Abstract: BRCA2 controls RAD51 recombinase during homologous DNA recombination (HDR) through eight evolutionarily conserved BRC repeats, which individually engage RAD51 via the motif Phe-x-x-Ala. Using structure-guided molecular design, templated on a monomeric thermostable chimera between human RAD51 and archaeal RadA, we identify CAM833, a 529 Da orthosteric inhibitor of RAD51:BRC with a Kd of 366 nM. The quinoline of CAM833 occupies a hotspot, the Phe-binding pocket on RAD51 and the methyl of the substituted α-methylbenzyl group occupies the Ala-binding pocket. In cells, CAM833 diminishes formation of damage-induced RAD51 nuclear foci; inhibits RAD51 molecular clustering, suppressing extended RAD51 filament assembly; potentiates cytotoxicity by ionizing radiation, augmenting 4N cell-cycle arrest and apoptotic cell death and works with poly-ADP ribose polymerase (PARP)1 inhibitors to suppress growth in BRCA2-wildtype cells. Thus, chemical inhibition of the protein-protein interaction between BRCA2 and RAD51 disrupts HDR and potentiates DNA damage-induced cell death, with implications for cancer therapy.	Mar 2021
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
I03-Macromolecular Crystallography	Using a fragment-based approach to identify alternative chemical scaffolds targeting dihydrofolate reductase from mycobacterium tuberculosis João A. Ribeiro , Alexander Hammer , Gerardo A. Libreros-Zúñiga , Sair M. Chavez-Pacheco , Petros Tyrakis , Gabriel S. De Oliveira , Timothy Kirkman , Jamal El Bakali , Silvana A. Rocco , Mauricio L. Sforça , Roberto Parise-Filho , Anthony G. Coyne , Tom L. Blundell , Chris Abell , Marcio V. B. Dias Acs Infectious Diseases DOI: 10.1021/acsinfecdis.0c00263 Show Abstract ▼ Abstract: Dihydrofolate reductase (DHFR), a key enzyme involved in folate metabolism, is a widely explored target in the treatment of cancer, immune diseases, bacteria, and protozoa infections. Although several antifolates have proved successful in the treatment of infectious diseases, they have been underexplored to combat tuberculosis, despite the essentiality of M. tuberculosis DHFR (MtDHFR). Herein, we describe an integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme. The application of a SAR by catalog strategy of an in house library for one of the identified fragments has led to a series of molecules that bind to MtDHFR with low micromolar affinities. Crystal structures of MtDHFR in complex with compounds of this series demonstrated a novel binding mode that considerably differs from other DHFR antifolates, thus opening perspectives for the development of relevant MtDHFR inhibitors.	Jul 2020
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification Sherine E. Thomas , Andrew J. Whitehouse , Karen Brown , Sophie Burbaud , Juan m Belardinelli , Jasper Sangen , Ramanuj Lahiri , Mark daben j. Libardo , Pooja Gupta , Sony Malhotra , Helena I. M. Boshoff , Mary Jackson , Chris Abell , Anthony g. Coyne , Tom L. Blundell , Rodrigo Andres Floto , Vitor Mendes Nucleic Acids Research 6 DOI: 10.1093/nar/gkaa539 Diamond Proposal Number(s): [9537, 14043, 18548] Open Access Show Abstract ▼ Abstract: Translational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically to kill bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and represents an attractive potential target for the development of new antibiotics. Here, we describe the application of a structure-guided fragment-based drug discovery approach to the design of a new class of inhibitors against TrmD in Mycobacterium abscessus. Fragment library screening, followed by structure-guided chemical elaboration of hits, led to the rapid development of drug-like molecules with potent in vitro TrmD inhibitory activity. Several of these compounds exhibit activity against planktonic M. abscessus and M. tuberculosis as well as against intracellular M. abscessus and M. leprae, indicating their potential as the basis for a novel class of broad-spectrum mycobacterial drugs.	Jun 2020
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Fragment-based design of Mycobacterium tuberculosis InhA inhibitors Mohamad Sabbah , Vitor Mendes , Robert G Vistal , David M. G. Dias , Monika Záhorszká , Katarína Mikušová , Jana Korduláková , Anthony G Coyne , Tom L. Blundell , Chris Abell Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00007 Diamond Proposal Number(s): [9537, 14043] Open Access Show Abstract ▼ Abstract: Tuberculosis (TB) remains a leading cause of mortality amongst infectious diseases worldwide. InhA, an enoyl ACP-reductase, has been the focus of numerous drug discovery efforts as this is the target of the first line pro-drug isoniazid. However, with resistance to this drug becoming more common the aim has been to find new clinical candidates that directly inhibit this enzyme and that do not require activation by the catalase peroxidase KatG, thus circumventing the majority of the resistance mechanisms. In this work, the screening and validation of a fragment library is described and development of the fragment hits using a fragment growing strategy was employed which led to the development InhA inhibitors with affinities of up to 250 nM.	Apr 2020
I02-Macromolecular Crystallography	Covalent inactivation of Mycobacterium thermoresistibile inosine-5′-monophosphate dehydrogenase (IMPDH) Ana Trapero , Angela Pacitto , Daniel Shiu-Hin Chan , Chris Abell , Tom L. Blundell , David B. Ascher , Anthony G. Coyne Bioorganic & Medicinal Chemistry Letters 30 DOI: 10.1016/j.bmcl.2019.126792 Diamond Proposal Number(s): [14043] Show Abstract ▼ Abstract: Inosine-5′-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme involved in nucleotide biosynthesis. Because of its critical role in purine biosynthesis, IMPDH is a drug design target for immunosuppressive, anticancer, antiviral and antimicrobial chemotherapy. In this study, we use mass spectrometry and X-ray crystallography to show that the inhibitor 6-Cl-purine ribotide forms a covalent adduct with the Cys-341 residue of Mycobacterium thermoresistibile IMPDH.	Jan 2020

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