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doi:10.22028/D291-38187
Titel: | Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening |
VerfasserIn: | Zhu, Di Johannsen, Sandra Masini, Tiziana Simonin, Céline Haupenthal, Jörg Illarionov, Boris Andreas, Anastasia Awale, Mahendra Gierse, Robin M. van der Laan, Tridia van der Vlag, Ramon Nasti, Rita Poizat, Mael Buhler, Eric Reiling, Norbert Müller, Rolf Fischer, Markus Reymond, Jean-Louis Hirsch, Anna K. H. |
Sprache: | Englisch |
Titel: | Chemical Science |
Bandnummer: | 13 |
Heft: | 36 |
Seiten: | 10686-10698 |
Verlag/Plattform: | Royal Society of Chemistry |
Erscheinungsjahr: | 2022 |
DDC-Sachgruppe: | 500 Naturwissenschaften |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | 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. |
DOI der Erstveröffentlichung: | 10.1039/D2SC02371G |
URL der Erstveröffentlichung: | https://pubs.rsc.org/en/content/articlelanding/2022/SC/D2SC02371G |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-381879 hdl:20.500.11880/34472 http://dx.doi.org/10.22028/D291-38187 |
ISSN: | 2041-6539 2041-6520 |
Datum des Eintrags: | 24-Nov-2022 |
Bezeichnung des in Beziehung stehenden Objekts: | Supplementary information |
In Beziehung stehendes Objekt: | https://www.rsc.org/suppdata/d2/sc/d2sc02371g/d2sc02371g1.pdf https://www.rsc.org/suppdata/d2/sc/d2sc02371g/d2sc02371g2.pdf https://www.rsc.org/suppdata/d2/sc/d2sc02371g/d2sc02371g3.pdf https://www.rsc.org/suppdata/d2/sc/d2sc02371g/d2sc02371g4.pdf |
Fakultät: | NT - Naturwissenschaftlich- Technische Fakultät |
Fachrichtung: | NT - Pharmazie |
Professur: | NT - Prof. Dr. Anna Hirsch NT - Prof. Dr. Rolf Müller |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Dateien zu diesem Datensatz:
Datei | Beschreibung | Größe | Format | |
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d2sc02371g.pdf | 2,6 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons