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

Nonato, Maria Cristina; Pádua, Ricardo Augusto Pereira de; David, Juliana S.; Reis, Renata A.G.; Tomaleri, Giovani Pinton; Pereira, H.M.

doi:10.1016/j.biochi.2019.01.006

Cited by 18 publications

(17 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The control of this disease is solely dependent on the chemotherapeutic drug praziquantel, which is used to treat infected individuals. There is no effective vaccine currently 3,9 . Other chemotherapy alternatives include oxamniquine and metrifonate, although these have some setbacks, such as being ineffective against all life stages of the parasite and severe side effects, which is why praziquantel is recommended [10][11][12][13][14][15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

“…Although praziquantel is effective, relatively safe and low cost, laboratory and field studies have shown the emergence of a resistant parasite strain in certain regions. This has led to a serious search for chemotherapeutic alternatives for the treatment and control of schistosomiasis 9,10 . Therefore, there is a need to search for alternatives using both laboratory and computational investigative methods to explore sequenced Schistosoma genomes 9 .…”

Section: Introductionmentioning

confidence: 99%

“…Schistosoma DHODH has been highly recommended as a druggable target that could offer alternative routes for schistosomiasis control 22,24 . Detailed structural differences have been demonstrated between human and Schistosoma DHODH 9 . Furthermore, Schistosoma mansoni cannot synthesize purine bases de novo, hence depends exclusively on the salvage pathway.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural, functional and docking analysis against Schistosoma mansoni dihydroorotate dehydrogenase for potential chemotherapeutic drugs

Otarigho

2019

F1000Res

View full text Add to dashboard Cite

Background: Praziquantel, as the only drug for the treatment of schistosomiasis, is under serious threat due to the emergence of resistant strains of Schistosoma species. There is an urgent need to search for alternative chemotherapy to supplement or complement praziquantel. Schistosoma dihydroorotate dehydrogenase (DHODH) has been recommended as a druggable target for schistosomiasis chemotherapy. The development of novel molecular modeling approaches, alongside with computational tools and rapid sequencing of pathogen genomes, have facilitated drug discovery. Therefore, the aim of this study was to employ computational approaches to screen compounds against Schistosoma mansoni DHODH. Methods: In this study, DHODH was used to blast on the latest version of DrugBank that contained 12,110 compounds, resulting in 26 drugs that can bind. Results: In silico docking shows that 13 drugs can bind strongly with an estimated free energy of binding, total intermolecular energy and estimated inhibition constant (Ki) greater than or equal to -8.6 kcal/mol, -8.12 kcal/mol and 1.12 µM, respectively. These compounds include the approved drugs manitimus, capecitabine, brequinar analog and leflunomide. Conclusions: These results indicate that these drugs have the potential for use in the control of schistosomiasis in the future.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structural, functional and docking analysis against Schistosoma mansoni dihydroorotate dehydrogenase for potential chemotherapeutic drugs

Otarigho

2019

F1000Res

View full text Add to dashboard Cite

show abstract

“…41 It is important to mention that previous work has been done regarding SmDHODH and HsDHODH by our laboratory (former master student Juliana S. David). 86,87 Data previously obtained (initial expression and purification protocols and biochemical characterization of the enzyme) has helped the development of this work. Kinetic parameters, previously determined ( Table 2) were used to set parameters for activity and inhibitory assays applied and also for the mechanism of inhibition.…”

Section: General Introductionmentioning

confidence: 99%

“…Cartoon representation of SmDHODH homology model 87. The hydrophobic N-terminal domain composed by two helices is illustrated in yellow.…”

mentioning

confidence: 99%

Reposicionamento de drogas antimaláricas no tratamento da esquistossomose baseado na inibição seletiva da enzima diidroorotato desidrogenase

Calil

View full text Add to dashboard Cite

Biochemical characterization of Mycobacterium tuberculosis dihydroorotate dehydrogenase and identification of a selective inhibitor

et al. 2023

View full text Add to dashboard Cite

Mycobacterium tuberculosis (MTB) is the etiologic agent of tuberculosis (TB), an ancient disease which causes 1.5 million deaths worldwide. Dihydroorotate dehydrogenase (DHODH) is a key enzyme of the MTB de novo pyrimidine biosynthesis pathway, and it is essential for MTB growth in vitro, hence representing a promising drug target. We present: (i) the biochemical characterization of the full‐length MTB DHODH, including the analysis of the kinetic parameters, and (ii) the previously unreleased crystal structure of the protein that allowed us to rationally screen our in‐house chemical library and identify the first selective inhibitor of mycobacterial DHODH. The inhibitor has fluorescence properties, potentially instrumental to in cellulo imaging studies, and exhibits an IC50 value of 43 μm, paving the way to hit‐to‐lead process.

show abstract

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

Cited by 18 publications

References 66 publications

Structural, functional and docking analysis against Schistosoma mansoni dihydroorotate dehydrogenase for potential chemotherapeutic drugs

Structural, functional and docking analysis against Schistosoma mansoni dihydroorotate dehydrogenase for potential chemotherapeutic drugs

Reposicionamento de drogas antimaláricas no tratamento da esquistossomose baseado na inibição seletiva da enzima diidroorotato desidrogenase

Biochemical characterization of Mycobacterium tuberculosis dihydroorotate dehydrogenase and identification of a selective inhibitor

Contact Info

Product

Resources

About