GLORIA — GEOMAR Library Ocean Research Information Access

1

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Protein‐Templated Dynamic Combinatorial Chemistry: Brief Overview and Experimental Protocol

Hartman, Alwin M. ; Gierse, Robin M. ; Hirsch, Anna K. H.

Wiley ; 2019

In: European Journal of Organic Chemistry Vol. 2019, No. 22 ( 2019-06-16), p. 3581-3590

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In: European Journal of Organic Chemistry, Wiley, Vol. 2019, No. 22 ( 2019-06-16), p. 3581-3590

Kurzfassung: Dynamic combinatorial chemistry (DCC) is a powerful tool to identify bioactive compounds. This efficient technique allows the target to select its own binders and circumvents the need for synthesis and biochemical evaluation of all individual derivatives. An ever‐increasing number of publications report the use of DCC on biologically relevant target proteins. This minireview complements previous reviews by focusing on the experimental protocol and giving detailed examples of essential steps and factors that need to be considered, such as protein stability, buffer composition and cosolvents.

Materialart: Online-Ressource

ISSN: 1434-193X , 1099-0690

URL: Issue

URL: Article

DOI: 10.1002/ejoc.v2019.22

DOI: 10.1002/ejoc.201900327

RVK:

VA 4073

Sprache: Englisch

Verlag: Wiley

Publikationsdatum: 2019

ZDB Id: 1475010-7

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2

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Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin

Jumde, Varsha R. ; Mondal, Milon ; Gierse, Robin M. ; [weitere]

Wiley ; 2018

In: ChemMedChem Vol. 13, No. 21 ( 2018-11-06), p. 2266-2270

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In: ChemMedChem, Wiley, Vol. 13, No. 21 ( 2018-11-06), p. 2266-2270

Kurzfassung: Acylhydrazone‐based dynamic combinatorial chemistry (DCC) is a powerful strategy for the rapid identification of novel hits. Even though acylhydrazones are important structural motifs in medicinal chemistry, their further progression in development may be hampered by major instability and potential toxicity under physiological conditions. It is therefore of paramount importance to identify stable replacements for acylhydrazone linkers. Herein, we present the first report on the design and synthesis of stable bioisosteres of acylhydrazone‐based inhibitors of the aspartic protease endothiapepsin as a follow‐up to a DCC study. The most successful bioisostere is equipotent, bears an amide linker, and we confirmed its binding mode by X‐ray crystallography. Having some validated bioisosteres of acylhydrazones readily available might accelerate hit‐to‐lead optimization in future acylhydrazone‐based DCC projects.

Materialart: Online-Ressource

ISSN: 1860-7179 , 1860-7187

URL: Issue

URL: Article

DOI: 10.1002/cmdc.v13.21

DOI: 10.1002/cmdc.201800446

RVK:

VA 3569

Sprache: Englisch

Verlag: Wiley

Publikationsdatum: 2018

ZDB Id: 2209649-8

SSG: 15,3

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3

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Druggability Assessment of Targets Used in Kinetic Target-Guided Synthesis

Unver, M. Yagiz ; Gierse, Robin M. ; Ritchie, Harry ; [weitere]

American Chemical Society (ACS) ; 2018

In: Journal of Medicinal Chemistry Vol. 61, No. 21 ( 2018-11-08), p. 9395-9409

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In: Journal of Medicinal Chemistry, American Chemical Society (ACS), Vol. 61, No. 21 ( 2018-11-08), p. 9395-9409

Materialart: Online-Ressource

ISSN: 0022-2623 , 1520-4804

URL: Article

DOI: 10.1021/acs.jmedchem.8b00266

DOI: 10.1021/acs.jmedchem.8b00266.s001

Sprache: Englisch

Verlag: American Chemical Society (ACS)

Publikationsdatum: 2018

ZDB Id: 1491411-6

SSG: 15,3

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4

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Hit-optimization using target-directed dynamic combinatorial chemistry: development of inhibitors of the anti-infective target 1-deoxy- d -xylulose-5-phosphate synthase

Jumde, Ravindra P. ; Guardigni, Melissa ; Gierse, Robin M. ; [weitere]

Royal Society of Chemistry (RSC) ; 2021

In: Chemical Science Vol. 12, No. 22 ( 2021), p. 7775-7785

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In: Chemical Science, Royal Society of Chemistry (RSC), Vol. 12, No. 22 ( 2021), p. 7775-7785

Materialart: Online-Ressource

ISSN: 2041-6520 , 2041-6539

URL: Article

DOI: 10.1039/D1SC00330E

Sprache: Englisch

Verlag: Royal Society of Chemistry (RSC)

Publikationsdatum: 2021

ZDB Id: 2559110-1

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5

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Not Every Hit‐Identification Technique Works on 1‐Deoxy‐ d ‐Xylulose 5‐Phosphate Synthase (DXPS): Making the Most of a Virtual Screening Campaign

Johannsen, Sandra ; Gierse, Robin M. ; Olshanova, Aleksandra ; [weitere]

Wiley ; 2023

In: ChemMedChem Vol. 18, No. 11 ( 2023-06)

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In: ChemMedChem, Wiley, Vol. 18, No. 11 ( 2023-06)

Kurzfassung: In this work, we demonstrate how important it is to investigate not only on‐target activity but to keep antibiotic activity against critical pathogens in mind. Since antimicrobial resistance is spreading in bacteria such as Mycobacterium tuberculosis , investigations into new targets are urgently needed. One promising new target is 1‐deoxy‐ d ‐xylulose 5‐phosphate synthase (DXPS) of the 2‐ C ‐methyl‐ d ‐erythritol 4‐phosphate (MEP) pathway. We have recently solved the crystal structure of truncated M. tuberculosis DXPS and used it to perform a virtual screening in collaboration with Atomwise Inc. using their deep convolutional neural network‐based AtomNet® platform. Of 94 virtual hit compounds only one showed interesting results in binding and activity studies. We synthesized 30 close derivatives using a straightforward synthetic route that allowed for easy derivatization. However, no improvement in activity was observed for any of the derivatives. Therefore, we tested them against a variety of pathogens and found them to be good inhibitors against Escherichia coli .

Materialart: Online-Ressource

ISSN: 1860-7179 , 1860-7187

URL: Issue

URL: Article

DOI: 10.1002/cmdc.v18.11

DOI: 10.1002/cmdc.202200590

RVK:

VA 3569

Sprache: Englisch

Verlag: Wiley

Publikationsdatum: 2023

ZDB Id: 2209649-8

SSG: 15,3

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6

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Identification of a 1-deoxy-D-xylulose-5-phosphate synthase (DXS) mutant with improved crystallographic properties

Gierse, Robin M. ; Reddem, Eswar R. ; Alhayek, Alaa ; [weitere]

Elsevier BV ; 2021

In: Biochemical and Biophysical Research Communications Vol. 539 ( 2021-02), p. 42-47

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In: Biochemical and Biophysical Research Communications, Elsevier BV, Vol. 539 ( 2021-02), p. 42-47

Materialart: Online-Ressource

ISSN: 0006-291X

URL: Article

DOI: 10.1016/j.bbrc.2020.12.069

RVK:

WA 15000

Sprache: Englisch

Verlag: Elsevier BV

Publikationsdatum: 2021

ZDB Id: 1461396-7

SSG: 12

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7

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Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening

Zhu, Di ; Johannsen, Sandra ; Masini, Tiziana ; [weitere]

Royal Society of Chemistry (RSC) ; 2022

In: Chemical Science Vol. 13, No. 36 ( 2022), p. 10686-10698

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In: Chemical Science, Royal Society of Chemistry (RSC), Vol. 13, No. 36 ( 2022), p. 10686-10698

Kurzfassung: In the present manuscript, we describe how we successfully used ligand-based virtual screening (LBVS) to identify two small-molecule, drug-like hit classes with excellent ADMET profiles against the difficult to address microbial enzyme 1-deoxy- d -xylulose-5-phosphate synthase (DXPS). In the fight against antimicrobial resistance (AMR), it has become increasingly important to address novel targets such as DXPS, the first enzyme of the 2- C -methyl- d -erythritol-4-phosphate (MEP) pathway, which affords the universal isoprenoid precursors. This pathway is absent in humans but essential for pathogens such as Mycobacterium tuberculosis , making it a rich source of drug targets for the development of novel anti-infectives. Standard computer-aided drug-design tools, frequently applied in other areas of drug development, often fail for targets with large, hydrophilic binding sites such as DXPS. Therefore, we introduce the concept of pseudo-inhibitors, combining the benefits of pseudo-ligands (defining a pharmacophore) and pseudo-receptors (defining anchor points in the binding site), for providing the basis to perform a LBVS against M. tuberculosis DXPS. Starting from a diverse set of reference ligands showing weak inhibition of the orthologue from Deinococcus radiodurans DXPS, we identified three structurally unrelated classes with promising in vitro (against M. tuberculosis DXPS) and whole-cell activity including extensively drug-resistant strains of M. tuberculosis . The hits were validated to be specific inhibitors of DXPS and to have a unique mechanism of inhibition. Furthermore, two of the hits have a balanced profile in terms of metabolic and plasma stability and display a low frequency of resistance development, making them ideal starting points for hit-to-lead optimization of antibiotics with an unprecedented mode of action.

Materialart: Online-Ressource

ISSN: 2041-6520 , 2041-6539

URL: Article

DOI: 10.1039/D2SC02371G

Sprache: Englisch

Verlag: Royal Society of Chemistry (RSC)

Publikationsdatum: 2022

ZDB Id: 2559110-1

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8

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Structure of Mycobacterium tuberculosis 1-Deoxy-D-Xylulose 5-Phosphate Synthase in Complex with Butylacetylphosphonate

Gawriljuk, Victor Oliveira ; Oerlemans, Rick ; Gierse, Robin M. ; [weitere]

MDPI AG ; 2023

In: Crystals Vol. 13, No. 5 ( 2023-04-27), p. 737-

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In: Crystals, MDPI AG, Vol. 13, No. 5 ( 2023-04-27), p. 737-

Kurzfassung: Stagnation in the development of new antibiotics emphasizes the need for the discovery of drugs with novel modes of action that can tackle antibiotic resistance. Contrary to humans, most bacteria use the methylerythritol phosphate (MEP) pathway to synthesize crucial isoprenoid precursors. 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) catalyzes the first and rate-limiting step of the pathway, making it an attractive target. Alkylacetylphosphonates (alkylAPs) are a class of pyruvate mimicking DXPS inhibitors that react with thiamin diphosphate (ThDP) to form a stable phosphonolactyl (PLThDP) adduct. Here, we present the first M. tuberculosis DXPS crystal structure in complex with an inhibitor (butylacetylphosphonate (BAP)) using a construct with improved crystallization properties. The 1.6 Å structure shows that the BAP adduct interacts with catalytically important His40 and several other conserved residues of the active site. In addition, a glycerol molecule, present in the D-glyceraldehyde 3-phosphate (D-GAP) binding site and within 4 Å of the BAP adduct, indicates that there is space to extend and develop more potent alkylAPs. The structure reveals the BAP binding mode and provides insights for enhancing the activity of alkylAPs against M. tuberculosis, aiding in the development of novel antibiotics.

Materialart: Online-Ressource

ISSN: 2073-4352

URL: Article

DOI: 10.3390/cryst13050737

Sprache: Englisch

Verlag: MDPI AG

Publikationsdatum: 2023

ZDB Id: 2661516-2

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9

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First crystal structures of 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization

Gierse, Robin M. ; Oerlemans, Rick ; Reddem, Eswar R. ; [weitere]

Springer Science and Business Media LLC ; 2022

In: Scientific Reports Vol. 12, No. 1 ( 2022-05-04)

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In: Scientific Reports, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2022-05-04)

Kurzfassung: The development of drug resistance by Mycobacterium tuberculosis and other pathogenic bacteria emphasizes the need for new antibiotics. Unlike animals, most bacteria synthesize isoprenoid precursors through the MEP pathway. 1-Deoxy- d -xylulose 5-phosphate synthase (DXPS) catalyzes the first reaction of the MEP pathway and is an attractive target for the development of new antibiotics. We report here the successful use of a loop truncation to crystallize and solve the first DXPS structures of a pathogen, namely M. tuberculosis ( Mt DXPS). The main difference found to other DXPS structures is in the active site where a highly coordinated water was found, showing a new mechanism for the enamine-intermediate stabilization. Unlike other DXPS structures, a “fork-like” motif could be identified in the enamine structure, using a different residue for the interaction with the cofactor, potentially leading to a decrease in the stability of the intermediate. In addition, electron density suggesting a phosphate group could be found close to the active site, provides new evidence for the D-GAP binding site. These results provide the opportunity to improve or develop new inhibitors specific for Mt DXPS through structure-based drug design.

Materialart: Online-Ressource

ISSN: 2045-2322

URL: Article

DOI: 10.1038/s41598-022-11205-9

Sprache: Englisch

Verlag: Springer Science and Business Media LLC

Publikationsdatum: 2022

ZDB Id: 2615211-3

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10

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Homo-timeric structural model of human microsomal prostaglandin E synthase-1 and characterization of its substrate/inhibitor binding interactions

Xing, Li ; Kurumbail, Ravi G. ; Frazier, Ronald B. ; [weitere]

Springer Science and Business Media LLC ; 2009

In: Journal of Computer-Aided Molecular Design Vol. 23, No. 1 ( 2009-1), p. 13-24

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In: Journal of Computer-Aided Molecular Design, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2009-1), p. 13-24

Materialart: Online-Ressource

ISSN: 0920-654X , 1573-4951

URL: Article

DOI: 10.1007/s10822-008-9233-4

Sprache: Englisch

Verlag: Springer Science and Business Media LLC

Publikationsdatum: 2009

ZDB Id: 2008643-X

SSG: 12

SSG: 15,3

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