A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis

Pooja Gupta, Sherine E. Thomas, Shaymaa A. Zaidan, Maria A. Pasillas, James Cory-Wright, Víctor Sebastián-Pérez, Ailidh Burgess, Emma Cattermole, Clio Meghir, Chris Abell, Anthony G. Coyne, William R. Jacobs, Tom L. Blundell, Sangeeta Tiwari, Vítor Mendes

Research output: Contribution to journalArticlepeer-review

Abstract

The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) of Mycobacterium tuberculosis are rapidly sterilised in mice, while inhibition of ArgJ with Pranlukast was found to clear chronic M. tuberculosis infection in a mouse model. Enzymes in the arginine biosynthetic pathway have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is assessed using a fragment-based approach. We identify several hits against these enzymes validated with biochemical and biophysical assays, as well as X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity against M. tuberculosis. These results demonstrate the potential for more enzymes in this pathway to be targeted with dedicated drug discovery programmes.

Original languageEnglish (US)
Pages (from-to)3491-3506
Number of pages16
JournalComputational and Structural Biotechnology Journal
Volume19
DOIs
StatePublished - Jan 2021

Keywords

  • ArgB
  • ArgC
  • ArgD
  • ArgF
  • FBDD
  • Mycobacterium tuberculosis

ASJC Scopus subject areas

  • Biotechnology
  • Biophysics
  • Structural Biology
  • Biochemistry
  • Genetics
  • Computer Science Applications

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