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  3. A new strategy for hit generation: Novel in cellulo active inhibitors of CYP121A1 from Mycobacterium tuberculosis via a combined X-ray crystallographic and phenotypic screening approach (XP screen)

A new strategy for hit generation: Novel in cellulo active inhibitors of CYP121A1 from Mycobacterium tuberculosis via a combined X-ray crystallographic and phenotypic screening approach (XP screen)

  • Eur J Med Chem. 2022 Feb 15;230:114105. doi: 10.1016/j.ejmech.2022.114105.
Martyn Frederickson 1,  Irwin R Selvam 2,  Dimitrios Evangelopoulos 3,  Kirsty J McLean 2,  Mona M Katariya 1,  Richard B Tunnicliffe 2,  Bethany Campbell 1,  Madeline E Kavanagh 1,  Sitthivut Charoensutthivarakul 1,  Richard T Blankley 4,  Colin W Levy 5,  Luiz Pedro S de Carvalho 3,  David Leys 2,  Andrew W Munro 6,  Anthony G Coyne 7,  Chris Abell 1
Affiliations

Affiliations

  • 1 Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom.
  • 2 Department of Chemistry, Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester, M1 7DN, United Kingdom.
  • 3 Mycobacterium Metabolism and Antibiotic Research Laboratory, Francis Crick Institute, 1 Midland Road, London, NW1 1AT, United Kingdom.
  • 4 Agilent Technologies U.K. Ltd, 5500 Lakeside, Cheadle Royal, Cheshire, SK8 3GR, United Kingdom.
  • 5 Manchester Protein Structure Facility (MPSF), Manchester Institute of Biotechnology, University of Manchester, Manchester, M1 7DN, United Kingdom.
  • 6 Department of Chemistry, Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester, M1 7DN, United Kingdom. Electronic address: andrew.munro@manchester.ac.uk.
  • 7 Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom. Electronic address: agc40@cam.ac.uk.
PMID: 35065413 DOI: 10.1016/j.ejmech.2022.114105
Abstract

There is a pressing need for new drugs against tuberculosis (TB) to combat the growing resistance to current antituberculars. Herein a novel strategy is described for hit generation against promising TB targets involving X-ray crystallographic screening in combination with phenotypic screening. This combined approach (XP Screen) affords both a validation of target engagement as well as determination of in cellulo activity. The utility of this method is illustrated by way of an XP Screen against CYP121A1, a Cytochrome P450 enzyme from Mycobacterium tuberculosis (Mtb) championed as a validated drug discovery target. A focused screening set was synthesized and tested by such means, with several members of the set showing promising activity against Mtb strain H37Rv. One compound was observed as an X-ray hit against CYP121A1 and showed improved activity against Mtb strain H37Rv under multiple assay conditions (pan-assay activity). Data obtained during X-ray crystallographic screening were utilized in a structure-based campaign to design a limited number of analogues (less than twenty), many of which also showed pan-assay activity against Mtb strain H37Rv. These included the benzo[b][1,4]oxazine derivative (MIC90 6.25 μM), a novel hit compound suitable as a starting point for a more involved hit to lead candidate medicinal chemistry campaign.

Keywords

CYP121; Drug discovery; Mycobacterium tuberculosis; Tuberculosis; X-ray crystallography.

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