Antileishmanial natural products as potential inhibitors of the Leishmania pteridine reductase: insights from molecular docking and molecular dynamics simulations.

Although many natural product-derived compounds possess anti-leishmanial activities in vitro and in vivo, their molecular targets in the Leishmania parasite remain elusive. This is a major challenge in optimizing these compounds into leads. The Leishmania pteridine reductase (PTR1) is peculiar for folate and pterin metabolism and has been validated as a drug target. In this study, 17 compounds with anti-leishmanial activities were screened against Leishmania major PTR1 (LmPTR1) using molecular docking and molecular dynamics (MD) simulations. All ligands were bound in the active site pocket of LmPTR1 with binding affinities ranging from -11.2 to -5.2 kcal/mol. Agnuside, betulin, betulinic acid, gerberinol, ismailin, oleanolic acid, pristimerin, and ursolic acid demonstrated binding affinities similar to a known inhibitor, methyl 1-(4-{[2,4-diaminopteridin-6-yl) methyl] amino} benzoyl) piperidine-4-carboxylate (DVP). MD simulations revealed that betulin, betulinic acid, ismailin, oleanolic acid, pristimerin, and ursolic acid formed stable complexes with LmPTR1. The binding free energies of the complexes were very good (-87 to -148 kJ/mol), and much higher than the complex of the standard DVP inhibitor and LmPTR1 (-27 kJ/mol). Betulin, betulinic acid, ismailin, oleanolic acid, pristimerin, and ursolic acid likely exert their antileishmanial action by inhibiting PTR1 and could thus be used as a basis for the development of potential antileishmanial chemotherapeutic agents.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00247-8.