Continuing our computational studies on a variety of target proteins from parasites causing neglected tropical diseases [1,2], the present study aimed at the in silico identification and subsequent in vitro evaluation of natural products (NPs) as potential lead structures for the development of novel inhibitors of pteridine reductase I from Leishmania major (LmPTR1), a peculiar enzyme of the folate metabolism in Leishmania species.
The in silico study was carried out employing a pharmacophore based virtual screening followed by molecular docking into the substrate site of LmPTR1 using about 1300 compounds from a commercial NP database and led to the identification of 11 flavonoids as potential inhibitors. In vitro evaluation of the in silico hits on recombinant LmPTR1 revealed significant inhibitory activity (> 20 % inhibition at 50 µM) for 8 (73 %) of the 11 tested flavonoids. Three of these compounds displayed IC50 below 50 µM against LmPTR1 (Fig. 1), with sophoraflavanone G being the most active (IC50 = 19.2 µM). The significant in vitro activity of flavonoids is in agreement with very recent data by Borsari et al. [3]. The compounds identified in the present study represent further promising lead structures for inhibitor development. Additionally, the obtained data allowed the elucidation of basic structure activity relationships of the tested flavonoids against LmPTR1.
Acknowledgements
Test compounds were kindly donated by Phytolab GmbH, Vestenbergsgreuth, Germany. Bacteria containing the expression plasmid for LmPTR1 were kindly provided by M.P. Costi (Modena, Italy).
Support of CCG (Montreal, Canada) is gratefully acknowledged.
This work is part of the activities of ResNetNPND: http://www.uni-muenster.de/ ResNetNPND/
Fig.1: Most active identified flavonoids
References:
[1] Herrmann F. C., Schmidt T. J. Planta Med. 2013; 79 1132
[2] Herrmann F. C. et al. Molecules 2015; 20(9) 16154-69
[3] Borsari C. et al., J. Med. Chem. 2016; 59 7598-7616