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


Type
Article
Change log
Authors
Gupta, Pooja 
Thomas, Sherine E 
Zaidan, Shaymaa A 
Pasillas, Maria A 
Cory-Wright, James 
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.

Description
Keywords
ASU, asymmetric unit, ArgB, ArgC, ArgD, ArgF, DSF, Differential scanning fluorimetry, FBDD, FBDD, Fragment-based drug discovery, ITC, Isothermal titration calorimetry, Mycobacterium tuberculosis, NMR, Nuclear magnetic resonance, SPR, Surface plasmon resonance, TB, tuberculosis
Journal Title
Comput Struct Biotechnol J
Conference Name
Journal ISSN
2001-0370
2001-0370
Volume Title
19
Publisher
Elsevier BV
Sponsorship
Wellcome Trust (200814/Z/16/Z)