Crystallographic approach to fragment-based hit discovery against Schistosoma mansoni purine nucleoside phosphorylase

DOI: 10.1042/BCJ20210041

Authors: Muhamamd Faheem (National University of Medical Sciences) , Napoleao Fonseca Valadares (Universidade de Brasília) , Jose Brandao-Neto (Diamond Light Source) , Domenico Bellini (MRC Harwell) , Patrick Collins (Diamond Light Source) , Nicholas M. Pearce (SGC Oxford) , Louise Bird (Diamond Light Source) , Juliana Torini De Souza (Universidade de Sao Paulo Campus de Sao Carlos) , Raymond Owens (Diamond Light Source) , Humberto Pereira (Universidade de São Paulo) , Frank Von Delft (Diamond Light Source) , João Alexandre Ribeiro Gonçalves Barbosa (Universidade de Brasilia)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemical Journal

State: Published (Approved)
Published: September 2021
Diamond Proposal Number(s): 11175

Abstract: Several Schistosoma species cause Schistosomiasis, an endemic disease in 78 countries that is ranked second amongst the parasitic diseases in terms of its socioeconomic impact and human health importance. The drug recommended for treatment by the WHO is praziquantel (PZQ), but there are concerns associated with PZQ, such as the lack of information about its exact mechanism of action, its high price, its effectiveness – which is limited to the parasite’s adult form – and reports of resistance. The parasites lack the de novo purine pathway, rendering them dependent on the purine salvage pathway or host purine bases for nucleotide synthesis. Thus, the Schistosoma purine salvage pathway is an attractive target for the development of necessary and selective new drugs. In this study, the purine nucleotide phosphorylase II (PNP2), a new isoform of PNP1, was submitted to a high-throughput fragment-based hit discovery using a crystallographic screening strategy. PNP2 was crystallized and crystals were soaked with 827 fragments, a subset of the Maybridge 1000 library. X-ray diffraction data was collected and structures were solved. Out of 827-screened fragments we have obtained a total of 19 fragments that show binding to PNP2. 14 of these fragments bind to the active site of PNP2, while five were observed in three other sites. Here we present the first fragment screening against PNP2.

Journal Keywords: Schistosoma mansoni; fragment screening; purine nucleoside phosphorylase; PNP2; X-ray crystallography

Diamond Keywords: Schistosomiasis; Enzymes

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 21/09/2021 09:49

Documents:
bcj-2021-0041.pdf

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening