Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening
Articolo
Data di Pubblicazione:
2022
Citazione:
Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening / D. Zhu, S. Johannsen, T. Masini, C. Simonin, J. Haupenthal, B. Illarionov, A. Andreas, M. Awale, R.M. Gierse, T. van der Laan, R. van der Vlag, R. Nasti, M. Poizat, E. Buhler, N. Reiling, R. Muller, M. Fischer, J. Reymond, A.K.H. Hirsch. - In: CHEMICAL SCIENCE. - ISSN 2041-6520. - 13:36(2022 Aug), pp. 10686-10698. [10.1039/d2sc02371g]
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 antiinfectives. 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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Tuberculosis; MEP; DXPS; ligand-based virtual screening
Elenco autori:
D. Zhu, S. Johannsen, T. Masini, C. Simonin, J. Haupenthal, B. Illarionov, A. Andreas, M. Awale, R.M. Gierse, T. van der Laan, R. van der Vlag, R. Nasti, M. Poizat, E. Buhler, N. Reiling, R. Muller, M. Fischer, J. Reymond, A.K.H. Hirsch
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