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

Author:

Zhu Di123,Johannsen Sandra12ORCID,Masini Tiziana3,Simonin Céline4,Haupenthal Jörg1,Illarionov Boris5,Andreas Anastasia12,Awale Mahendra4,Gierse Robin M.123ORCID,van der Laan Tridia6,van der Vlag Ramon3ORCID,Nasti Rita3,Poizat Mael7,Buhler Eric8ORCID,Reiling Norbert910,Müller Rolf1211ORCID,Fischer Markus5ORCID,Reymond Jean-Louis4,Hirsch Anna K. H.12311ORCID

Affiliation:

1. Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) – Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, 66123 Saarbrücken, Germany

2. Department of Pharmacy, Saarland University, Campus Building E8.1, 66123 Saarbrücken, Germany

3. Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands

4. Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland

5. Hamburg School of Food Science, Institute of Food Chemistry, Grindelallee 117, 20146 Hamburg, Germany

6. Department of Mycobacteria, National Institute of Public Health and the Environment (RIVM), Diagnostics and Laboratory Surveillance (IDS), Infectious Diseases Research, Antonie van Leeuwenhoeklaan 9, 3721 MA Bilthoven, The Netherlands

7. Symeres, Kadijk 3, 9747 AT Groningen, The Netherlands

8. Laboratoire Matière et Systèmes Complexes (MSC), UMR CNRS 7057, Université Paris Cité, Bâtiment Condorcet, 75205 Paris Cedex 13, France

9. RG Microbial Interface Biology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany

10. German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany

11. Helmholtz International Lab for Anti-infectives, Campus Building E8.1, 66123 Saarbrücken, Germany

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.

Funder

H2020 European Research Council

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Publisher

Royal Society of Chemistry (RSC)

Subject

General Chemistry

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