التفاصيل البيبلوغرافية
| العنوان: |
Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis |
| المؤلفون: |
Cécile Exertier, Alessandra Salerno, Lorenzo Antonelli, Annarita Fiorillo, Riccardo Ocello, Francesca Seghetti, Jessica Caciolla, Elisa Uliassi, Matteo Masetti, Eleonora Fiorentino, Stefania Orsini, Trentina Di Muccio, Andrea Ilari, Maria Laura Bolognesi |
| سنة النشر: |
2024 |
| مصطلحات موضوعية: |
Biochemistry, Medicine, Pharmacology, Cancer, Infectious Diseases, Space Science, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, Physical Sciences not elsewhere classified, medicinal chemistry campaign, drug discovery approaches, trypanosoma brucei <, leishmania infantum <, ex vivo <, based drug discovery, 9 , 14 , 10 , tr binding site, leishmaniasis trypanothione reductase, vitro <, silico <, k <, , tr inhibition, suitable target, still challenging, potent inhibitors, improve selectivity, difficult target |
| الوصف: |
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 1 – 3 , which provided ideal starting points for a medicinal chemistry campaign. In silico 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 4 – 14 . A trend of improvement in Leishmania infantum TR inhibition was detected along the optimization and confirmed by the crystal structures of 9 , 10 , and 14 in complex with Trypanosoma brucei TR. Compound 10 showed the best TR inhibitory profile ( K i = 0.2 μM), whereas 9 was the best one in terms of in vitro and ex vivo activity. Although further fine-tuning is needed to improve selectivity, we demonstrated the potentiality of FBDD on a classic but difficult target for leishmaniasis. |
| نوع الوثيقة: |
dataset |
| اللغة: |
unknown |
| Relation: |
https://figshare.com/articles/dataset/Fragment_Merging_Growing_and_Linking_Identify_New_Trypanothione_Reductase_Inhibitors_for_Leishmaniasis/24925510 |
| DOI: |
10.1021/acs.jmedchem.3c01439.s007 |
| الاتاحة: |
https://doi.org/10.1021/acs.jmedchem.3c01439.s007
https://figshare.com/articles/dataset/Fragment_Merging_Growing_and_Linking_Identify_New_Trypanothione_Reductase_Inhibitors_for_Leishmaniasis/24925510 |
| Rights: |
CC BY-NC 4.0 |
| رقم الانضمام: |
edsbas.94B84C4 |
| قاعدة البيانات: |
BASE |