Crystal structure of Schistosoma purine nucleoside phosphorylase complexed with a novel monocyclic inhibitor

Author(s)

Pereira, Humberto M. ^{[1, 2]} ; Berdini, Valerio ^[3] ; Ferri, Mariana R. ^[2] ; Cleasby, Anne ^[3] ; Garratt, Richard C. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Fis Sao Carlos, BR-13560970 Sao Carlos, SP - Brazil

^[2] UNICEP, Ctr Univ Cent Paulista, Sao Paulo - Brazil

^[3] Astex Therapeut, Cambridge - England

• Document type: Journal article
• Source: Acta Tropica; v. 114, n. 2, p. 97-102, MAY 2010.
• Web of Science Citations: 13

Abstract

A novel inhibitor of Schistosoma PNP was identified using an ``in silico{''} approach allied to enzyme inhibition assays. The compound has a monocyclic structure which has not been previously described for PNP inhibitors The crystallographic structure of the complex was determined and used to elucidate the binding mode within the active site Furthermore, the predicted pose was very similar to that determined crystallographically, validating the methodology The compound Sm\_VS1, despite its low molecular weight, possesses an IC(50) of 1 3 mu M, surprisingly low when compared with purine analogues This is presumably due to the formation of eight hydrogen bonds with key residues in the active site E203, N245 and T244. The results of this study highlight the importance of the use of multiple conformations for the target during virtual screening. Indeed the Sm\_VS1 compound was only identified after flipping the N245 side chain It is expected that the structure will be of use in the development of new highly active non-purine based compounds against the Sclustosoma enzyme. (c) 2010 Elsevier B V. All rights reserved (AU)

• FAPESP's process: 98/14138-2 - Center for Structural Molecular Biotechnology
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC