Fragment-based target screening as an empirical approach to prioritising targets: a case study on antibacterials

Canning, P.; Birchall, Kristian; Kettleborough, Catherine A.; Merritt, Andy; Coombs, P.J.

doi:10.1016/j.drudis.2020.09.003

Cited by 11 publications

(5 citation statements)

References 21 publications

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“…Fragments are potent chemical tools that can efficaciously explore the surface of proteins for new binding sites and their chemical space, even with small libraries of a few hundreds of compounds and can consequently be employed to assess the ligandability of protein targets [18] , [42] . Therefore, this approach was employed to assess the ligandability of ArgB, ArgC, ArgD and ArgF, and to identify potential starting points for fragment elaboration.…”

Section: Discussionmentioning

confidence: 99%

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

Gupta

Thomas

Zaidan

et al. 2021

Computational and Structural Biotechnology Journal

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Section: Discussionmentioning

confidence: 99%

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

Gupta

Thomas

Zaidan

et al. 2021

Computational and Structural Biotechnology Journal

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“…Fragment screening campaigns prove particularly useful in cases (1) when there is no prior knowledge of structural information on either a therapeutic target or corresponding ligands, (2) when there is a need to identify or explore novel chemical entities, (3) to access the druggability of diverse targets, or (4) when other drug discovery approaches were either not applicable or failed to give meaningful outcomes. In its still young history, FBDD has been a promising and effective solution in those situations and has led to several remarkable success stories. − Achieving reliable and sufficiently high hit rates is crucial for subsequent elaboration efforts and strongly connected to careful library design.…”

Section: Resultsmentioning

confidence: 99%

Fragtory: Pharmacophore-Focused Design, Synthesis, and Evaluation of an sp³-Enriched Fragment Library

et al. 2023

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Fragment-based drug discovery has played an important role in medicinal chemistry and pharmaceutical research. Despite numerous demonstrated successes, the limited diversity and overrepresentation of planar, sp 2 -rich structures in commercial libraries often hamper the full potential of this approach. Hence, the thorough design of screening libraries inevitably determines the probability for meaningful hits and subsequent structural elaboration. Against this background, we present the generation of an exclusive fragment library based on iterative entry nomination by a specifically designed computational workflow: "FRAGTORY". Following a pharmacophore diversity-driven approach, we used FRAGTORY in an interdisciplinary academic setting to guide both tailored synthesis efforts and the implementation of in-house compounds to build a curated 288-member library of sp 3enriched fragments. Subsequent NMR screens against a model protein and hit validation by protein crystallography led to the identification of structurally novel ligands that were further characterized by isothermal titration calorimetry, demonstrating the applicability of our experimental approach.

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“…Fragments are potent chemical tools that can efficaciously explore the surface of proteins for new binding sites and their chemical space, even with small libraries of a few hundreds of compounds and can therefore be employed to assess the ligandability of protein targets (18,41). Therefore, this approach was employed to assess the ligandability of ArgB, ArgC, ArgD and ArgF, to identify potential starting points for fragment development.…”

Section: Discussionmentioning

confidence: 99%

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

Gupta

Thomas

Cory-Wright

et al. 2021

Preprint

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The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine, appears to be attractive target for anti-Tuberculosis (TB) drug discovery. Starvation of M. tuberculosis deleted for either argB or argF genes led to rapid sterilization of these strains in mice while Chemical inhibition of ArgJ with Pranlukast was also found to clear chronic M. tuberculosis infection in animal models. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is explored using a fragment-based approach. We reveal several hits for these enzymes validated with biochemical and biophysical assays, and 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 of more enzymes in this pathway to be targeted with dedicated drug discovery programmes.

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Fragment-based target screening as an empirical approach to prioritising targets: a case study on antibacterials

Cited by 11 publications

References 21 publications

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

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

Fragtory: Pharmacophore-Focused Design, Synthesis, and Evaluation of an sp³-Enriched Fragment Library

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

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Fragment-based target screening as an empirical approach to prioritising targets: a case study on antibacterials

Cited by 11 publications

References 21 publications

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

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

Fragtory: Pharmacophore-Focused Design, Synthesis, and Evaluation of an sp3-Enriched Fragment Library

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

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Fragtory: Pharmacophore-Focused Design, Synthesis, and Evaluation of an sp³-Enriched Fragment Library