Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening. Issue 36 (7th September 2022)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Chemical science. Volume 13:Issue 36(2022)
• Page Start: 10686
• Page End: 10698
• Publication Date: 2022-09-07
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d2sc02371g
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : We identified two drug-like antitubercular hits with submicromolar inhibition constants against the target 1-deoxy-d -xylulose-5-phosphate synthase (DXPS) with a new mode of action and promising activity against drug-resistant tuberculosis. 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.