Fragment library screening by X-ray crystallography and binding site analysis on thioredoxin glutathione reductase of Schistosoma mansoni

DOI: 10.1038/s41598-024-52018-2

Authors: Lauro Ribeiro De Souza Neto (Oswaldo Cruz Institute, FIOCRUZ) , Bogar Omar Montoya (Oswaldo Cruz Institute, FIOCRUZ) , Jose Brandao-Neto (Diamond Light Source; Research Complex at Harwell) , Anil Verma (The Wellcome Centre for Human Genetics, University of Oxford) , Sebastian Bowyer (London School of Hygiene and Tropical Medicine) , José Teófilo Moreira-Filho (Universidade Federal de Goiás) , Rafael Ferreira Dantas (Oswaldo Cruz Institute, FIOCRUZ) , Bruno Junior Neves (Universidade Federal de Goiás) , Carolina Horta Andrade (Universidade Federal de Goiás; University of São Paulo) , Frank Von Delft (Diamond Light Source; Research Complex at Harwell; University of Oxford; University of Johannesburg) , Raymond J. Owens (The Wellcome Centre for Human Genetics, University of Oxford; Rosalind Franklin Institute) , Nicholas Furnham (London School of Hygiene and Tropical Medicine) , Floriano Paes Silva-Jr (Oswaldo Cruz Institute, FIOCRUZ)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 14

State: Published (Approved)
Published: January 2024

Abstract: Schistosomiasis is caused by parasites of the genus Schistosoma, which infect more than 200 million people. Praziquantel (PZQ) has been the main drug for controlling schistosomiasis for over four decades, but despite that it is ineffective against juvenile worms and size and taste issues with its pharmaceutical forms impose challenges for treating school-aged children. It is also important to note that PZQ resistant strains can be generated in laboratory conditions and observed in the field, hence its extensive use in mass drug administration programs raises concerns about resistance, highlighting the need to search for new schistosomicidal drugs. Schistosomes survival relies on the redox enzyme thioredoxin glutathione reductase (TGR), a validated target for the development of new anti-schistosomal drugs. Here we report a high-throughput fragment screening campaign of 768 compounds against S. mansoni TGR (SmTGR) using X-ray crystallography. We observed 49 binding events involving 35 distinct molecular fragments which were found to be distributed across 16 binding sites. Most sites are described for the first time within SmTGR, a noteworthy exception being the “doorstop pocket” near the NADPH binding site. We have compared results from hotspots and pocket druggability analysis of SmTGR with the experimental binding sites found in this work, with our results indicating only limited coincidence between experimental and computational results. Finally, we discuss that binding sites at the doorstop/NADPH binding site and in the SmTGR dimer interface, should be prioritized for developing SmTGR inhibitors as new antischistosomal drugs.

Journal Keywords: Biochemistry; Biophysics; Biotechnology; Chemical biology; Computational biology and bioinformatics; Drug discovery; Enzymes; Parasitic infection; Structural biology

Diamond Keywords: Schistosomiasis; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 22/01/2024 09:57

Documents:
s41598-024-52018-2.pdf

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Structural biology Biophysics Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)