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

Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Structural basis of prolyl hydroxylase domain inhibition by molidustat William D. Figg , Michael A. Mcdonough , Rasheduzzaman Chowdhury , Yu Nakashima , Zhihong Zhang , James P. Holt‐martyn , Alen Krajnc , Christopher J. Schofield Chemmedchem 5 DOI: 10.1002/cmdc.202100133 Diamond Proposal Number(s): [18069] Open Access Show Abstract ▼ Abstract: Human prolyl‐hydroxylases (PHDs) are hypoxia‐sensing 2‐oxoglutarate (2OG) oxygenases, catalysis by which suppresses the transcription of hypoxia‐inducible factor target genes. PHD inhibition enables the treatment of anaemia/ischaemia‐related disease. The PHD inhibitor Molidustat is approved for the treatment of renal anaemia; it differs from other approved/late‐stage PHD inhibitors in lacking a glycinamide side chain. The first reported crystal structures of Molidustat and IOX4 (a brain‐penetrating derivative) complexed with PHD2 reveal how their contiguous triazole, pyrazolone and pyrimidine/pyridine rings bind at the active site. The inhibitors bind to the active‐site metal in a bidentate manner through their pyrazolone and pyrimidine nitrogens, with the triazole π‐π‐stacking with Tyr303 in the 2OG binding pocket. Comparison of the new structures with other PHD inhibitor complexes reveals differences in the conformations of Tyr303, Tyr310, and a mobile loop linking β2–β3, which are involved in dynamic substrate binding/product release.	Apr 2021
Krios I-Titan Krios I at Diamond	Malaria pigment crystals: The achilles′ heel of the malaria parasite Sergey Kapishnikov , Ernst Hempelmann , Michael Elbaum , Jens Als‐nielsen , Leslie Leiserowitz Chemmedchem 4 DOI: 10.1002/cmdc.202000895 Open Access Show Abstract ▼ Abstract: The biogenic formation of hemozoin crystals, a crucial process in heme detoxification by the malaria parasite, is reviewed as an antimalarial drug target. We first focus on the in‐vivo formation of hemozoin. A model is presented, based on native‐contrast 3D imaging obtained by X‐ray and electron microscopy, that hemozoin nucleates at the inner membrane leaflet of the parasitic digestive vacuole, and grows in the adjacent aqueous medium. Having observed quantities of hemoglobin and hemozoin in the digestive vacuole, we present a model that heme liberation from hemoglobin and hemozoin formation is an assembly‐line process. The crystallization is preceded by reaction between heme monomers yielding hematin dimers involving fewer types of isomers than in synthetic hemozoin; this is indicative of protein‐induced dimerization. Models of antimalarial drugs binding onto hemozoin surfaces are reviewed. This is followed by a description of bromoquine, a chloroquine drug analogue, capping a significant fraction of hemozoin surfaces within the digestive vacuole and accumulation of the drug, presumably a bromoquine–hematin complex, at the vacuole's membrane.	Mar 2021
I04-1-Macromolecular Crystallography (fixed wavelength)	Deliberately losing control of C−H activation processes in the design of small‐molecule‐fragment arrays targeting peroxisomal metabolism Raysa Khan Tareque , Storm Hassell-Hart , Tobias Krojer , Anthony Bradley , Srikannathasan Velupillai , Romain Talon , Michael Fairhead , Iain J. Day , Kamlesh Bala , Robert Felix , Paul D. Kemmitt , Paul Brennan , Frank Von Delft , Laura Diaz Saez , Kilian Huber , John Spencer Chemmedchem 15, 2513 - 2520 DOI: 10.1002/cmdc.v15.24 Diamond Proposal Number(s): [18145] Show Abstract ▼ Abstract: Combined photochemical arylation, “nuisance effect” (SNAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium‐throughput X‐ray protein–ligand structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho‐arylation of 2‐phenylpyridine gave five products resulting from mono‐ and bisarylations combined with SNAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.	Aug 2020
I24-Microfocus Macromolecular Crystallography	Diphenylene iodonium is a non‐covalent MAO inhibitor: a biochemical and structural analysis Luca Giacinto Iacovino , Joana Reis , Antonello Mai , Claudia Binda , Andrea Mattevi Chemmedchem DOI: 10.1002/cmdc.202000264 Diamond Proposal Number(s): [20221] Show Abstract ▼ Abstract: Diphenylene iodonium (DPI) is known for its inhibitory activities against many flavin‐ and heme‐dependent enzymes and is often used as an NADPH oxidase inhibitor. We probed the efficacy of DPI on two well‐known drug targets, the human monoamine oxidases MAO A and B. UV‐visible spectrophotometry and steady‐state kinetics experiments demonstrate that DPI acts as a competitive MAO inhibitor with Ki values of 1.7 µM and 0.3 µM for MAO A and MAO B, respectively. Elucidation of the crystal structure of human MAO B bound to the inhibitor revealed that DPI binds deeply in the active‐site cavity to establish multiple hydrophobic interactions with the surrounding side chains and the flavin. These data prove that DPI is a genuine MAO inhibitor and the inhibition mechanism does not involve a reaction with the reduced flavin. This binding and inhibitory activity against MAOs, two major ROS‐producing enzymes, will have to be carefully considered when interpreting experiments that rely on DPI for target validation and chemical biology studies on ROS functions.	May 2020
I24-Microfocus Macromolecular Crystallography	Elucidation of an allosteric mode‐of‐action for a thienopyrazole RORγt inverse agonist Rens M. J. M. De Vries , Femke A. Meijer , Richard G. Doveston , Luc Brunsveld Chemmedchem DOI: 10.1002/cmdc.202000044 Open Access Show Abstract ▼ Abstract: The demand for allosteric targeting of nuclear receptors is high, but examples are limited, and structural information is scarce. The retinoic acid‐related orphan receptor gamma t (RORγt) is an important transcriptional regulator for the differentiation of T helper 17 cells for which the first, and some of the most promising, examples of allosteric nuclear receptor modulation have been reported and structurally proven. In a 2015 patent, filed by the pharmaceutical company Glenmark, a new class of small molecules was reported that act as potent inverse agonists for RORγt. A compound library around the central thienopyrazole scaffold captured a clear structure‐activity relationship, but the binding mechanism of this new class of RORγt modulators has not been elucidated. Using a combination of biochemical and X‐ray crystallography studies, here the allosteric mechanism for the inverse agonism for the most potent compound, classified in the patent as “example 13”, is reported, providing a strongly desired additional example of allosteric nuclear receptor targeting.	Feb 2020
I03-Macromolecular Crystallography	Structure‐activity relationship and crystallographic studies on 4‐hydroxypyrimidine HIF prolyl hydroxylase domain inhibitors James P. Holt‐martyn , Rasheduzzaman Chowdhury , Anthony Tumber , Tzu‐lan Yeh , Martine I. Abboud , Kerstin Lippl , Christopher T. Lohans , Gareth W. Langley , William Figg , Michael A. Mcdonough , Christopher W. Pugh , Peter J. Ratcliffe , Christopher J. Schofield Chemmedchem 13 DOI: 10.1002/cmdc.201900557 Open Access Show Abstract ▼ Abstract: The 2‐oxoglutarate‐dependent hypoxia inducible factor prolyl hydroxylases (PHDs) are targets for treatment of a variety of diseases including anaemia. One PHD inhibitor is approved for use for the treatment of renal anaemia and others are in late stage clinical trials. The number of reported templates for PHD inhibition is limited. We report structure–activity relationship and crystallographic studies on a promising class of 4‐hydroxypyrimidine‐containing PHD inhibitors.	Dec 2019
I03-Macromolecular Crystallography	Molecular recognition of a Thomsen-Friedenreich antigen mimetic targeting human galectin-3 Sabrina Santarsia , Ana Sofia Grosso , Filipa Trovão , Jesús Jiménez-Barbero , Ana Luisa Carvalho , Cristina Nativi , Filipa Marcelo Chemmedchem DOI: 10.1002/cmdc.201800525 Diamond Proposal Number(s): [16609] Show Abstract ▼ Abstract: Overexpression of the Thomsen‐Friedenreich (TF) antigen in cell membrane proteins occurs in 90% of adenocarcinomas. Additionally, the binding of the TF‐antigen to human galectin‐3 (Gal‐3), also frequently overexpressed in malignancy, promotes cancer progression and metastasis. In this context, structures that interfere with this specific interaction display the potential to prevent cancer metastasis. Herein, a multidisciplinary approach, combining the optimized synthesis of a TF‐antigen mimetic with NMR, X‐ray crystallography methods and isothermal titration calorimetry assays has been employed to unravel the molecular structural details that govern the Gal‐3/TF‐mimetic interaction. The TF‐mimetic presents a binding affinity for Gal‐3 similar to the TF‐natural antigen and retains the binding epitope and the bioactive conformation observed for the native antigen. Furthermore, from a thermodynamic perspective a decrease in the enthalpic contribution was observed for the Gal‐3/TF‐mimetic complex, however this behaviour is compensated by a favourable entropy gain. From a structural perspective, these results establish our TF‐mimetic as a scaffold to design multivalent solutions to potentially interfere with Gal‐3 aberrant interactions and likely be used to hamper Gal‐3‐mediated cancer cells adhesion and metastasis.	Aug 2018
I04-1-Macromolecular Crystallography (fixed wavelength)	Identifying small molecule binding sites for epigenetic proteins at domain-domain interfaces Paul Brennan , David Bowkett , Romain Talon , Cynthia Tallant , Chris Schofield , Gordon Bruton , Frank Von Delft , Stefan Knapp Chemmedchem DOI: 10.1002/cmdc.201800030 Open Access Show Abstract ▼ Abstract: Epigenetics is of rapidly growing field in drug discovery. Of particular interest is the role of post‐translational modifications to histone and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains, is that with the notable exception of bromodomains, they tend not to possess a well enclosed binding site amenable to small molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains there are opportunities for designing inhibitors that bind at a domain‐domain interface which provide a more suitable interaction pocket. Examination of X‐ray structures of multiple domains involved in recognizing and modifying post‐translational histone marks using the SiteMap algorithm identified potential binding sites at domain‐domain interfaces. For the tandem plant homeodomain‐bromodomain of SP100C, a potential inter‐domain site identified computationally was validated experimentally by the discovery of ligands by X‐ray crystallographic fragment screening.	Mar 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
I02-Macromolecular Crystallography	Inhibitors against fungal cell wall remodeling enzymes Ignacio Delso , Jessika Valero-Gonzalez , Fernando Gomollón-Bel , Jorge Castro-López , Wenxia Fang , Iva Navratilova , Daan M F Van Aalten , Tomás Tejero , Pedro Merino , Ramon Hurtado-Guerrero Chemmedchem 6 DOI: 10.1002/cmdc.201700720 Diamond Proposal Number(s): [10121] Show Abstract ▼ Abstract: Fungal β-1,3-glucan glucanosyltransferases are glucan-remodeling enzymes that play important roles in cell wall integrity, and are essential for the viability of pathogenic fungi and yeasts. As such, they are considered possible drug targets, although inhibitors of this class of enzymes have not yet been reported. Herein we report a multidisciplinary approach based on a structure-guided design using a highly conserved transglycosylase from Sacharomyces cerevisiae, that leads to carbohydrate derivatives with high affinity for Aspergillus fumigatus Gel4. We demonstrate by X-ray crystallography that the compounds bind in the active site of Gas2/Gel4 and interact with the catalytic machinery. The topological analysis of noncovalent interactions demonstrates that the combination of a triazole with positively charged aromatic moieties are important for optimal interactions with Gas2/Gel4 through unusual pyridinium cation–π and face-to-face π–π interactions. The lead compound is capable of inhibiting AfGel4 with an IC50 value of 42 μm.	Dec 2017

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