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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Structural basis for the design of selective inhibitors for Schistosoma mansoni dihydroorotate dehydrogenase

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Nonato, M. Cristina [1] ; de Padua, Ricardo A. P. [1] ; David, Juliana S. [1] ; Reis, Renata A. G. [1] ; Tomaleri, Giovani P. [1] ; Pereira, Humberto D'Muniz [2] ; Calil, Felipe A. [1]
Total Authors: 7
[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Lab Cristalog Prot, Av Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil
[2] Univ Sao Paulo, Inst Fis Sao Carlos, Ctr Biotecnol Mol Estrutural, BR-13560970 Sao Carlos, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: Biochimie; v. 158, p. 180-190, MAR 2019.
Web of Science Citations: 3

Trematode worms of the genus Schistosoma are the causing agents of schistosomiasis, a parasitic disease responsible for a considerable economic and healthy burden worldwide. In the present work, the characterization of the enzyme dihydroorotate dehydrogenase from Schistosoma mansoni (SmDHODH) is presented. Our studies demonstrated that SmDHODH is a member of class 2 DHODHs and catalyzes the oxidation of dihydroorotate into orotate using quinone as an electron acceptor by employing a ping-pong mechanism of catalysis. SmDHODH homology model showed the presence of all structural features reported for class 2 DHODH enzymes and reveal the presence of an additional protuberant domain predicted to fold as a flexible loop and absent in the other known class 2 DHODHs. Molecular dynamics simulations showed that the ligand-free forms of SmDHODH and HsDHODH undergo different rearrangements in solution. Well-known class 2 DHODH inhibitors were tested against SmDHODH and HsDHODH and the results suggest that the variable nature of the quinone-binding tunnel between human and parasite enzymes, as well as the differences in structural plasticity involving rearrangements of the N-terminal alpha-helical domain can be exploited for the design of SmDHODH selective inhibitors, as a strategy to validate DHODH as a drug target against schistosomiasis. (C) 2019 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. (AU)

FAPESP's process: 11/14269-6 - Crystallographic studies of Dihydroorotate dehydrogenase from schistosoma mansoni
Grantee:Giovani Pinton Tomaleri
Support type: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 15/25099-5 - Antimalarial drug repositioning in the schistosomiasis treatment based on the selective inhibition of the enzyme dihydroorotate dehydrogenase
Grantee:Felipe Antunes Calil
Support type: Scholarships in Brazil - Doctorate