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

• Published in: Computational and structural biotechnology journal Vol. 19; pp. 3491 - 3506
• Main Authors: Gupta, Pooja, Thomas, Sherine E., Zaidan, Shaymaa A., Pasillas, Maria A., Cory-Wright, James, Sebastián-Pérez, Víctor, Burgess, Ailidh, Cattermole, Emma, Meghir, Clio, Abell, Chris, Coyne, Anthony G., Jacobs, William R., Blundell, Tom L., Tiwari, Sangeeta, Mendes, Vítor
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2021; Research Network of Computational and Structural Biotechnology; Elsevier
• Subjects: ArgB; ArgC; ArgD; ArgF; FBDD; Mycobacterium tuberculosis; ArgD; NMR; ArgC; ASU; ArgB; SPR; Mycobacterium tuberculosis; DSF; ITC; FBDD; TB; ArgF; NMR, Nuclear magnetic resonance; DSF, Differential scanning fluorimetry; ITC, Isothermal titration calorimetry; FBDD, Fragment-based drug discovery; SPR, Surface plasmon resonance; ASU, asymmetric unit; TB, tuberculosis
• ISSN: 2001-0370; 2001-0370
• DOI: 10.1016/j.csbj.2021.06.006

[Display omitted] 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.