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Study of the inhibition of the accumulation of cyclic nucleotide by pyridopyrimidine derivatives using molecular dynamics simulations

Grant number: 17/02201-4
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): January 01, 2018
Effective date (End): December 31, 2020
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Gilberto de Nucci
Grantee:Ivan Pires de Oliveira
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

In developing/underdeveloped countries, or in places where natural disasters or armed conflicts occur, high rates of mortality are observed related to complications in cases of diarrhea, leading to the death of about 2 and a half million children every year, mainly caused by the infection with enterotoxigenic strains of Escherichia coli. The recommended treatments involve: (1) oral hydration, with replacement of electrolytes (sodium and potassium) and glucose; (2) administration of antimicrobial and peristalsis reducing agents. The first line of treatment, however, which involves hydration, is highly dependent on the access to large volumes of potable water, which is often unavailable in the locations described above. In the case of the currently used pharmacological treatment, there are also disadvantages related to the selection of resistant microorganisms and constipation. Fortunately, some pyridopyrimidine derivatives have shown promise as treatment agents of the conditions associated with diarrhea. These new compounds have been tested experimentally, and they were capable of inhibiting the accumulation of cyclic nucleotides in the biochemical cascade associated with diarrhea. In this mechanism, the enterotoxin STa arising from E. coli strains binds to the receptor of the particulate guanylate cyclase, stimulating the synthesis of cGMP in the intestinal cells. And excess intracellular cGMP deregulates the osmotic control, leading to diarrhea. Until the present time, however, the action mechanism related to the inhibition of the accumulation of cGMP in the intestinal cells is not understood, and this is the main goal of this project. To study this mechanism, we will use molecular dynamics simulations as a tool, linking it to the experimental results available in the literature (studies carried out by Ferid Murad and collaborators, in particular) and data obtained for the new pyridopyrimidine derivatives by the research group of Prof. Gilberto De Nucci using in vitro assays (currently, only these two researchers have significant results with these compounds). We will investigate the molecular interactions of the pyridopyrimidine derivatives with three target proteins: guanylate cyclase, tyrosine kinase and phosphodiesterase type 5, taking the relationship of these proteins with the synthesis or consumption of cGMP into account. In this sense, we hope to contribute with relevant information that may shed light on the action mechanisms of these compounds, and enable the development of more effective molecules for the treatment of diarrhea through this new pharmacological approach. (AU)

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Scientific publications (16)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
YAHAGI, SILVIA S.; ROVEDA, ANA C.; SOBRAL, ADRIELLI T.; OLIVEIRA, IVAN P.; CAIRES, ANDERSON R. L.; GOMES, ROBERTO S.; TRINDADE, MAGNO A. G.. An Analytical Evaluation of the Synergistic Effect on Biodiesel Oxidation Stability Promoted by Binary and Ternary Blends Containing Multifunctional Additives. INTERNATIONAL JOURNAL OF ANALYTICAL CHEMISTRY, . (17/02201-4)
DE OLIVEIRA, IVAN PIRES; LIMA CAIRES, ANDERSON RODRIGUES. Molecular arrangement in diesel/biodiesel blends: A Molecular Dynamics simulation analysis. RENEWABLE ENERGY, v. 140, p. 203-211, . (17/02201-4)
MEZACASA, A. V.; QUEIROZ, A. M.; GRACIANO, D. E.; PONTES, M. S.; SANTIAGO, E. F.; OLIVEIRA, I. P.; LOPEZ, A. J.; CASAGRANDE, G. A.; SCHERER, M. D.; DOS REIS, D. D.; et al. Effects of gold nanoparticles on photophysical behaviour of chlorophyll and pheophytin. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY A-CHEMISTRY, v. 389, . (17/02201-4)
DE OLIVEIRA, IVAN PIRES; MARTINEZ, LEANDRO. The shift in urea orientation at protein surfaces at low pH is compatible with a direct mechanism of protein denaturation. Physical Chemistry Chemical Physics, v. 22, n. 1, p. 354-367, . (17/02201-4, 18/24293-0, 10/16947-9, 13/08293-7)
PARADA, CAROLINA A.; DE OLIVEIRA, IVAN PIRES; GEWEHR, MAYARA C. F.; MACHADO-NETO, JOAO AGOSTINHO; LIMA, KELI; EICHLER, ROSANGELA A. S.; LOPES, LUCIA R.; BECHARA, LUIZ R. G.; FERREIRA, JULIO C. B.; FESTUCCIA, WILLIAM T.; et al. ffect of FKBP12-Derived Intracellular Peptides on Rapamycin-Induced FKBP-FRB Interaction and Autophag. ELL, v. 11, n. 3, . (19/25049-9, 13/07937-8, 19/27149-0, 17/02201-4, 16/04000-3, 19/07332-5, 19/23864-7)
LESCANO, CAROLINE HONAISER; DE LIMA, FERNANDO FREITAS; CARDOSO, CLAUDIA ANDREA LIMA; VIEIRA, SILVIA CRISTINA HEREDIA; MONICA, FABIOLA ZAKIA; DE OLIVEIRA, IVAN PIRES. Rutin present in Alibertia edulis extract acts on human platelet aggregation through inhibition of cyclooxygenase/thromboxane. FOOD & FUNCTION, v. 12, n. 2, p. 802-814, . (17/26687-3, 18/12121-0, 17/02201-4, 20/01237-8)
ROVEDA, ANA CAROLINA; DE OLIVEIRA, IVAN PIRES; LIMA CAIRES, ANDERSON RODRIGUES; RINALDO, DANIEL; FERREIRA, VALDIR SOUZA; TRINDADE, MAGNO APARECIDO GONCALVES. Improving butylhydroxytoluene activity with alternative secondary antioxidants: High synergistic effect in stabilizing biodiesel/diesel fuel blends in the presence of pro-oxidative metal. INDUSTRIAL CROPS AND PRODUCTS, v. 178, p. 11-pg., . (17/02201-4)
DE OLIVEIRA, IVAN PIRES; LESCANO, CAROLINE HONAISER; DE NUCCI, GILBERTO. In Silico Mapping of Essential Residues in the Catalytic Domain of PDE5 Responsible for Stabilization of Its Commercial Inhibitors. SCIENTIA PHARMACEUTICA, v. 87, n. 4, . (13/22360-9, 10/16947-9, 13/08293-7, 13/05475-7, 17/02201-4, 17/26687-3)
DE OLIVEIRA, IVAN PIRES; DE NUCCI, GILBERTO. Inhibition of cyclic nucleotide accumulation induced by pyridopyrimidine derivatives: Analysis of MD simulations for peptide STa, enzyme PDE5, and sGC. British Journal of Pharmacology, v. 177, n. 11, p. 3-pg., . (17/02201-4)
AGALYA, P.; DE OLIVEIRA, I. PIRES; LESCANO, C. H.; CAIRES, A. R. L.; VELUSAMY, V.. ffect of pH and cosolvent sucralose on the solvation profile of ovalbumin: Ultrasonic and molecular simulation studie. FOOD HYDROCOLLOIDS, v. 125, . (17/26687-3, 17/02201-4)
DE OLIVEIRA, IVAN PIRES; LIMA CAIRES, ANDERSON RODRIGUES; BASKAR, KARTHICK; PONNUSAMY, SASIKUMAR; LAKSHMANAN, PALANIAPPAN; VEERAPPAN, VELUSAMY. Biodiesel as an additive for diesel-ethanol (diesohol) blend: physical-chemical parameters and origin of the fuels' miscibility. FUEL, v. 263, . (17/02201-4)
PONTES, MONTCHARLES S.; ANTUNES, DEBORA R.; OLIVEIRA, IVAN P.; FORINI, MARIANA M. L.; SANTOS, JAQUELINE S.; ARRUDA, GILBERTO J.; CAIRES, ANDERSON R. L.; SANTIAGO, ETENALDO F.; GRILLO, RENATO. Chitosan/tripolyphosphate nanoformulation carrying paraquat: insights on its enhanced herbicidal activity. ENVIRONMENTAL SCIENCE-NANO, v. 8, n. 5, p. 1336-1351, . (17/02201-4, 20/12769-0, 17/21004-5, 11/01872-6)
LESCANO, CAROLINE HONAISER; DE LIMA, FERNANDO FREITAS; STEFANELLO CATELAN, TALINE BAGANHA; DANTAS GUIMARAES, VICTOR HUGO; ALVES PEREIRA, ULISSES; MARTINS AGUILAR, CHARLES; LIMA CARDOSO, CLAUDIA ANDREA; SOUSA SANTOS, SERGIO HENRIQUE; BORGES, ALEXANDRE; PIRES DE OLIVEIRA, IVAN. Campomanesia guazumifolia infusion decreases human platelet aggregation by reducing cyclooxygenase 1 activity and its underlying mechanisms. FOOD BIOSCIENCE, v. 55, p. 12-pg., . (17/02201-4, 18/12121-0, 17/26687-3, 20/01237-8)
JUSTO, ALBERTO FERNANDO O.; COLLACO, RITA DE CASSIA; LESCANO, CAROLINE HONAISER; DE OLIVEIRA, IVAN PIRES. Malignant neoplasm of breast in Brazilian women: A cross-sectional study from 2008 to 2019. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, v. 115, n. 1, p. 8-pg., . (17/02201-4, 17/26687-3, 16/09539-8)
YAHAGI, SILVIA S.; ROVEDA, ANA C.; SOBRAL, ADRIELLI T.; OLIVEIRA, IVAN P.; CAIRES, ANDERSON R. L.; GOMES, ROBERTO S.; TRINDADE, MAGNO A. G.. An Analytical Evaluation of the Synergistic Effect on Biodiesel Oxidation Stability Promoted by Binary and Ternary Blends Containing Multifunctional Additives. INTERNATIONAL JOURNAL OF ANALYTICAL CHEMISTRY, v. 2019, p. 10-pg., . (17/02201-4)
LESCANO, CAROLINE H.; DE LIMA, FERNANDO FREITAS; MENDES-SILVERIO, CAMILA B.; JUSTO, ALBERTO F. O.; BALDIVIA, DEBORA DA SILVA; VIEIRA, CRISTIANO P.; SANJINEZ-ARGANDONA, ELIANA J.; CARDOSO, CLAUDIA A. L.; MONICA, FABIOLA Z.; DE OLIVEIRA, IVAN PIRES. Effect of Polyphenols From Campomanesia adamantium on Platelet Aggregation and Inhibition of Cyclooxygenases: Molecular Docking and in Vitro Analysis. FRONTIERS IN PHARMACOLOGY, v. 9, . (17/02201-4)

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