“Ligand fishing” in chemical space reveals new potential leishmanicidals

Abstract

Pteridine reductase 1 (PTR1) is suggested to be a potential drug target in Leishmania parasites, because it is predicted to be essential for the pathogen's survival and it appears to lack human homologues [1]. The aim of this study is to elucidate if “ligand fishing” in chemical space using ChemGPS-NP can be used to find new potential PTR1-inhibitors of natural origin. PTR1 in complex with 7,8-dihydrobiopterin (DHB), was obtained from the Protein Data Bank. Two sets of compounds, A and B, of natural origin were retrieved using ChemGPS-NP. ChemGPS-NP positions compounds in ch emical space according to their physical-chemical properties [2,3]. Group A included natural compounds that are positioned near DHB. Group B included natural compounds positioned far from all ligands in all crystalized structures of PTR1. The inhibitory effects of the compounds in group A and B, on PTR1 were assessed by predicting their affinity towards the enzyme using molecular docking. Thirteen of the 78 compounds in Group A were predicted to bind with a higher affinity than DHB to PTR1, and nine of these, interacted with the binding pocket of PTR1 in other ways than known ligands. None of the 191 compounds in Group B, were predicted to bind to PTR1 with the same or higher affinity than DHB. Hence, “ligand fishing” in chemical space using DHB as bait can be a successful path for finding new potential PTR1 inhibitors of natural origin.