Untargeted LC-MS metabolomic studies of Asteraceae species to discover inhibitors of Leishmania major dihydroorotate dehydrogenase

Author(s)

Chibli, Lucas A. ^[1] ; Rosa, Annylory L. ^[1] ; Nonato, Maria Cristina ^[2] ; Da Costa, Fernando B. ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, AsterBioChem Res Team, Ave Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Lab Prot Crystallog, Ave Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: METABOLOMICS; v. 15, n. 4 APR 2019.
• Web of Science Citations: 0

Abstract

Introduction Interesting data about the family Asteraceae as a new source of Leishmania major dihydroorotate dehydrogenase (LmDHODH) inhibitors are presented. This key macromolecular target for parasites causing neglected diseases catalyzes the fourth reaction of the de novo pyrimidine biosynthetic pathway, which takes part in major cell functions, including DNA and RNA biosynthesis. Objectives We aimed to (1) determine LmDHODH inhibitor candidates, revealing the type of chemistry underlying such bioactivity, and (2) predict the inhibitory potential of extracts from new untested plant species, classifying them as active or inactive based on their LC-MS based metabolic fingerprints. Methods Extracts from 150 species were screened for the inhibition of LmDHODH, and untargeted UHPLC-(ESI)-HRMS metabolomic studies were carried out in combination with in silico approaches. Results The IC50 values determined for a subset of 59 species ranged from 148 mu gmL(-1) to 9.4mgmL(-1). Dereplication of the metabolic fingerprints allowed the identification of 48 metabolites. A reliable OPLS-DA model (R-2>0.9, Q(2)>0.7, RMSECV<0.3) indicated the inhibitor candidates; nine of these metabolites were identified using data from isolated chemical standards, one of which4,5-di-O-E-caffeoylquinic acid (IC50 73 mu M)was capable of inhibiting LmDHODH. The predictive OPLS model was also effective, with 60% correct predictions for the test set. Conclusion Our approach was validated for (1) the discovery of LmDHODH inhibitors or interesting starting points for the optimization of new leishmanicides from Asteraceae species and (2) the prediction of extracts from untested species, classifying them as active or inactive. (AU)

• FAPESP's process: 14/26866-7 - Metabolomics, enzymatic targets and in silico tools in the search of bioactive compounds from plants
• Grantee: Fernando Batista da Costa
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/01443-6 - Screening of inhibitors of trypanosomatides DHODHs enzymes in Asteraceae employing metabolomics combined with in silico methods
• Grantee: Lucas Apolinário Chibli
• Support Opportunities: Scholarships in Brazil - Doctorate