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Screening of inhibitors of trypanosomatides DHODHs enzymes in Asteraceae employing metabolomics combined with in silico methods

Grant number: 14/01443-6
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): November 01, 2014
Effective date (End): July 31, 2018
Field of knowledge:Health Sciences - Pharmacy - Pharmacognosy
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Fernando Batista da Costa
Grantee:Lucas Apolinário Chibli
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):16/18579-3 - Chemoinformatic tools applied for the screening of inhibitors of the enzyme DHODH from Leishmania major, BE.EP.DR


Neglected tropical diseases (NTDs) affect more than a billion people worldwide. Despite that few effective drugs are available to treat these diseases, especially those caused by trypanosomatides, such as Chagas disease (Trypanosoma cruzi) and leishmaniose (Leishmania spp.). The flavoenzyme dihydroorotate dehydrogenase (DHODH) is a potential molecular target for antiprotozoal substances screening. Plants from Asteraceae and its isolated substances have antiprotozoal activity and therefore great DHODHs enzymes inhibition potential, for T. cruzi (TcDHODH) and L. major (LmDHODH). This potential was verified by our group in pilot in vitro tests done prior to the submission of this proposal. Considering this potential, the demand for active substances against NTDs and the need for chemical and pharmacological studies of native Cerrado species, we propose to screen plant extracts and isolated compounds from Asteraceae species for in vitro inhibition of the enzymes LmDHODH and TcDHODH, combined with metabolomic studies by UHPLC - UV - HRFTMS and in silico methods. This approach has proved to be extremely effective in screening bioactive natural products (NP), once the correlation analysis between the extracts fingerprints and the in vitro assays results determines, primarily, which substances may or not be responsible for the activity even before they are isolated, which would be hardly possible by conventional phytochemical methods. (AU)

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Scientific publications
(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)
CHIBLI, LUCAS A.; ROSA, ANNYLORY L.; NONATO, MARIA CRISTINA; DA COSTA, FERNANDO B.. Untargeted LC-MS metabolomic studies of Asteraceae species to discover inhibitors of Leishmania major dihydroorotate dehydrogenase. METABOLOMICS, v. 15, n. 4, . (14/26866-7, 14/01443-6)
CHIBLI, LUCAS A.; SCHMIDT, THOMAS J.; CRISTINA NONATO, M.; CALIL, FELIPE A.; DA COSTA, FERNANDO B.. Natural products as inhibitors of Leishmania major dihydroorotate dehydrogenase. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 157, p. 852-866, . (14/01443-6, 14/26866-7, 16/18579-3, 15/25099-5)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
CHIBLI, Lucas Apolinário. Screening of inhibitors of Leishmania major DHODH in Asteraceae: metabolomic studies and Quantitative Structure-Activity Relationships (QSAR).. 2018. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) Ribeirão Preto.

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