2. Academic Validation
  3. Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis

Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis

  • J Med Chem. 2024 Jan 11;67(1):402-419. doi: 10.1021/acs.jmedchem.3c01439.
Cécile Exertier 1,  Alessandra Salerno 2,  Lorenzo Antonelli 3,  Annarita Fiorillo 3,  Riccardo Ocello 2 4,  Francesca Seghetti 2,  Jessica Caciolla 2,  Elisa Uliassi 2,  Matteo Masetti 2,  Eleonora Fiorentino 5,  Stefania Orsini 5,  Trentina Di Muccio 5,  Andrea Ilari 1,  Maria Laura Bolognesi 2
Affiliations

Affiliations

  • 1 Institute of Molecular Biology and Pathology (IBPM) of the National Research Council of Italy (CNR), c/o Department of Biochemical Sciences, Sapienza University of Rome, Piazzale A. Moro 5, Roma 00185, Italy.
  • 2 Department of Pharmacy and Biotechnology, Alma Mater Studiorum─University of Bologna, Via Belmeloro 6, Bologna 40126, Italy.
  • 3 Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, Roma 00185, Italy.
  • 4 Computational and Chemical Biology, Istituto Italiano di Tecnologia, via Morego 30, Genova 16163, Italy.
  • 5 Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, Roma 00161, Italy.
PMID: 38164929 DOI: 10.1021/acs.jmedchem.3c01439
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 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 (Ki = 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.

Figures
Products