8PF5
Crystal structure of Trypanosoma brucei trypanothione reductase in complex with 1-(3,4-dichlorobenzyl)-4-(((5-((4-fluorophenethyl)carbamoyl)furan-2-yl)methyl)carbamoyl)-1-(3-phenylpropyl)piperazin-1-ium
Summary for 8PF5
| Entry DOI | 10.2210/pdb8pf5/pdb |
| Related | 8PF3 8PF4 |
| Descriptor | Trypanothione reductase, FLAVIN-ADENINE DINUCLEOTIDE, 4-[(3,4-dichlorophenyl)methyl]-~{N}-[[5-[2-(4-fluorophenyl)ethylcarbamoyl]furan-2-yl]methyl]-4-(3-phenylpropyl)-1,4$l^{4}-diazinane-1-carboxamide, ... (8 entities in total) |
| Functional Keywords | oxidoreductase activity, nucleotide binding, flavoenzyme, inhibitor binding, oxidoreductase |
| Biological source | Trypanosoma brucei More |
| Total number of polymer chains | 4 |
| Total formula weight | 220269.17 |
| Authors | Exertier, C.,Antonelli, L.,Fiorillo, A.,Ilari, A. (deposition date: 2023-06-15, release date: 2024-04-03, Last modification date: 2024-11-06) |
| Primary citation | Exertier, C.,Salerno, A.,Antonelli, L.,Fiorillo, A.,Ocello, R.,Seghetti, F.,Caciolla, J.,Uliassi, E.,Masetti, M.,Fiorentino, E.,Orsini, S.,Di Muccio, T.,Ilari, A.,Bolognesi, M.L. Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis. J.Med.Chem., 67:402-419, 2024 Cited by PubMed Abstract: Trypanothione reductase (TR) is a suitable target for drug discovery approaches against leishmaniasis, although the identification of potent inhibitors is still challenging. Herein, we harnessed a fragment-based drug discovery (FBDD) strategy to develop new TR inhibitors. Previous crystallographic screening identified fragments -, which provided ideal starting points for a medicinal chemistry campaign. investigations revealed critical hotspots in the TR binding site, guiding our structure- and ligand-based structure-actvity relationship (SAR) exploration that yielded fragment-derived compounds -. A trend of improvement in TR inhibition was detected along the optimization and confirmed by the crystal structures of , , and in complex with TR. Compound showed the best TR inhibitory profile ( = 0.2 μM), whereas was the best one in terms of and activity. Although further fine-tuning is needed to improve selectivity, we demonstrated the potentiality of FBDD on a classic but difficult target for leishmaniasis. PubMed: 38164929DOI: 10.1021/acs.jmedchem.3c01439 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.42 Å) |
Structure validation
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