{"doi":"10.1016/j.csbj.2021.06.006","title":"A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of <i>Mycobacterium tuberculosis</i>","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.","journal":"Computational and Structural Biotechnology Journal","year":2021,"id":171741,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9653,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":503197,"name":"S.E. Thomas","orcid":"0000-0003-1152-4312","position":1,"is_corresponding":false},{"id":707164,"name":"Shaymaa A. Zaidan","orcid":null,"position":2,"is_corresponding":false},{"id":707165,"name":"Maria A. Pasillas","orcid":null,"position":3,"is_corresponding":false},{"id":707166,"name":"J. Cory-Wright","orcid":null,"position":4,"is_corresponding":false},{"id":706634,"name":"Víctor Sebastián-Pérez","orcid":"0000-0002-8248-4496","position":5,"is_corresponding":false},{"id":706635,"name":"Ailidh Burgess","orcid":"0000-0002-9643-3163","position":6,"is_corresponding":false},{"id":706636,"name":"Emma Cattermole","orcid":"0000-0002-0671-2207","position":7,"is_corresponding":false},{"id":706637,"name":"C. Meghir","orcid":"0000-0002-1551-6726","position":8,"is_corresponding":false},{"id":331047,"name":"Chris Abell","orcid":"0000-0001-9174-1987","position":9,"is_corresponding":false},{"id":331046,"name":"Anthony G. Coyne","orcid":"0000-0003-0205-5630","position":10,"is_corresponding":false},{"id":361264,"name":"William R. Jacobs","orcid":"0000-0003-3321-3080","position":11,"is_corresponding":false},{"id":329601,"name":"Tom L. Blundell","orcid":"0000-0002-2708-8992","position":12,"is_corresponding":false},{"id":511439,"name":"Sangeeta Tiwari","orcid":"0000-0003-1727-8036","position":13,"is_corresponding":false},{"id":331041,"name":"V. Mendes","orcid":"0000-0002-2734-2444","position":14,"is_corresponding":false},{"id":503203,"name":"Pooja Gupta","orcid":"0000-0002-0944-4498","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-18T23:46:33.067299Z","pmid":"34194673","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}