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No endogenous ligands are known to bind this protein which does not present well-shaped binding sites, making it target particularly challenging to target. With the aim of targeting this peculiar system, we carried out two different screenings: (i) a fragment-based lead discovery campaign directed to the N-terminal as well as to the canonical binding site of 1CGrx1; (ii) a structure-based virtual screening directed to the 1CGrx1 canonical binding site. Here we report a small molecule that binds at the glutathione binding site in which the binding mode of the molecule was deeply investigated by Nuclear Magnetic Resonance (NMR). This compound represents an important step in the attempt to develop a novel strategy to interfere with the peculiar Trypanosoma Brucei redox system, making it possible to shed light on the perturbation of this biochemical machinery and eventually to novel therapeutic possibilities.<\/jats:p>","DOI":"10.3390\/molecules28031276","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T02:01:18Z","timestamp":1675044078000},"page":"1276","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Drugging the Undruggable Trypanosoma brucei Monothiol Glutaredoxin 1"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3085-1426","authenticated-orcid":false,"given":"Annagiulia","family":"Favaro","sequence":"first","affiliation":[{"name":"Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Bolcato","sequence":"additional","affiliation":[{"name":"Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5000-1333","authenticated-orcid":false,"given":"Marcelo A.","family":"Comini","sequence":"additional","affiliation":[{"name":"Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400, Uruguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7514-3802","authenticated-orcid":false,"given":"Stefano","family":"Moro","sequence":"additional","affiliation":[{"name":"Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8187-0264","authenticated-orcid":false,"given":"Massimo","family":"Bellanda","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy"},{"name":"Consiglio Nazionale delle Ricerche, Institute of Biomolecular Chemistry, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3944-0313","authenticated-orcid":false,"given":"Mattia","family":"Sturlese","sequence":"additional","affiliation":[{"name":"Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,28]]},"reference":[{"key":"ref_1","unstructured":"(2022, November 27). 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