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

Abstract

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)