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Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors.

Authors
  • Song, Lijun1
  • Merceron, Romain2
  • Hulpia, Fabian3
  • Lucía, Ainhoa4
  • Gracia, Begoña4
  • Jian, Yanlin5
  • Risseeuw, Martijn D P5
  • Verstraelen, Toon6
  • Cos, Paul7
  • Aínsa, José A4
  • Boshoff, Helena I8
  • Munier-Lehmann, Hélène9
  • Savvides, Savvas N10
  • Van Calenbergh, Serge11
  • 1 Laboratory for Medicinal Chemistry (FFW), Ghent University, Tergestensis 460, B-9000, Gent, Belgium; 3M, Zwijndrecht, Belgium. , (Belgium)
  • 2 VIB Center for Inflammation Research, Zwijnaarde, Ghent, 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Technologiepark 927, 9052, Zwijnaarde, Ghent, Belgium; Eurofins Group, Poitiers, France. , (Belgium)
  • 3 Laboratory for Medicinal Chemistry (FFW), Ghent University, Tergestensis 460, B-9000, Gent, Belgium; Janssen Pharmaceutica, Beerse, Belgium. , (Belgium)
  • 4 Grupo de Genética de Micobacterias, Departamento de Microbiología, Facultad de Medicina, and BIFI, Universidad de Zaragoza, Zaragoza, Spain; CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029, Madrid, Spain. , (Spain)
  • 5 Laboratory for Medicinal Chemistry (FFW), Ghent University, Tergestensis 460, B-9000, Gent, Belgium. , (Belgium)
  • 6 Center for Melecular Modeling, Ghent University, Zwijnaarde, Ghent, 9052, Belgium. , (Belgium)
  • 7 Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Department of Pharmaceutical Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, B-2610, Antwerpen, Belgium. , (Belgium)
  • 8 Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, United States. , (United States)
  • 9 CNRS UMR3523, Department of Structural Biology and Chemistry, Institut Pasteur, 75724, Paris Cedex 15, France. , (France)
  • 10 VIB Center for Inflammation Research, Zwijnaarde, Ghent, 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Technologiepark 927, 9052, Zwijnaarde, Ghent, Belgium. , (Belgium)
  • 11 Laboratory for Medicinal Chemistry (FFW), Ghent University, Tergestensis 460, B-9000, Gent, Belgium. Electronic address: [email protected] , (Belgium)
Type
Published Article
Journal
European journal of medicinal chemistry
Publication Date
Aug 18, 2021
Volume
225
Pages
113784–113784
Identifiers
DOI: 10.1016/j.ejmech.2021.113784
PMID: 34450493
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Mycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors. These efforts furnished the most potent MtTMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the MtTMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity. Copyright © 2021 Elsevier Masson SAS. All rights reserved.

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