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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: Biochimie; v. 158, p. 180-190, MAR 2019.
• Web of Science Citations: 3

Abstract

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 Opportunities: 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 Opportunities: Scholarships in Brazil - Doctorate