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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

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Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons Creative Commons