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

• Published in: Biochimie 2019-03, Vol.158, p.180-190
• Main Authors: Nonato, M. Cristina, de Pádua, Ricardo A.P., David, Juliana S., Reis, Renata A.G., Tomaleri, Giovani P., D'Muniz Pereira, Humberto, Calil, Felipe A.
• Format: Article
• Language: English
• Subjects: Dihydroorotate dehydrogenase; Enzyme kinetics; Homology modeling; Inhibitor; Schistosoma mansoni; Schistosomiasis
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/j.biochi.2019.01.006

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 α-helical domain can be exploited for the design of SmDHODH selective inhibitors, as a strategy to validate DHODH as a drug target against schistosomiasis. [Display omitted] •SmDHODH was evaluated by kinetic, homology modeling and molecular dynamics studies.•Class 2 SmDHODH converts dihydroorotate oxidation by following a ping-pong mechanism.•Conformational changes between HsDHODH and SmDHODH can grant drug selectivity.•Atovaquone was identified as a selective SmDHODH inhibitor in nanomolar range.•Atovaquone analogues can be used to search for drug leads against schistosomiasis.