In silico analyses of sesquiterpene-related compounds against pteridine reductase (PTR1)

Leishmania parasites are trypanosomatid protozoa that cause the neglected disease leishmaniasis, which infects 15 million people wordwide in three clinical forms. In spite of great efforts on selective targeting for antileishmanial activity, an effective/secure treatment has not already been found. However, rational design and/or searching for organic compounds with leishmanicidal potential remains as a key step in lead finding from nature. On this context, folate reduction by pteridine reductase (PTR1) as alternative metabolic route has been established when folate reductase has been inhibited. Thus, PTR1 can be considered as an important target for antileishmanial activity. Several sesquiterpene (ST)-related compounds isolated from natural sources have shown in vitro effectivity against promastigotes and amastigotes of Leishmania and in vivo activity. However, their mode of action has not been elucidated. Therefore, 123 antileishmanial STs were submitted to an in-silico study through molecular docking with PTR1. Results showed that ST-coumarins and xanthanolides are promissory leads for the PTR1 inhibition purposes (affinity values < -10 kcal/mol). Complexes share H-bond interactions with Ser111, being a crucial contact for the ST:enzyme complex stabilization. The protein:ligand interactions profiles exhibited a common receptor contact, through Phe113, which contributes to the non-polar stabilization in the hydrophobic moiety. The pharmacophore properties of ST and the residues involved in the binding pocket will be also discussed. The results are an excellent starting point for future studies of structural optimization of STs and demonstrate that PTR1 is as pharmacologically important target on chemotherapy against leishmaniasis in the route of a new research perspective towards therapeutic development of antileishmanial drugs.

Acknowledgements: The present work is a product derived by the Project CIAS-1331 financed by Vicerrectoría de Investigaciones at UMNG – Validity 2014.

Keywords: Molecular Docking, Sesquiterpenes, PTR1