Design, identification and validation of thioredoxin glutathione reductase modulators : a novel target for the management of schistosomiasis

Abstract

Scistosomiasis is a tropical parasitic disease currently treated solely with praziquantel. This has raised concerns regarding drug resistance. The thioredoxin glutathione reductase (TGR) enzyme is an enzyme present in schistosoma that has been identified as a target for 1-(2-hydroxyethyl) piperazine (HEPE) derivatives. The objective of this study was to investigate the TGR enzyme as a target for inhibition in the treatment of schistosomiasis, using two HEPE derivatives as lead molecules. Two crystallographic depositions, 6FMU and 6FMZ, describing the interactions between 2-[4-(2-hydroxyethyl)piperazin-1- yl]ethanol (DVK) and 2-[4-(4azanylbutyl)piperazin-1-yl]ethanol (DVQ) with the schistosomiatic TGR enzyme were identified. In the Virtual Screening (VS) approach, using SYBYL®-X, a consensus pharmacophore was generated using the two lead molecules. This was used to query the ZincPharmer® database with filters for leadlikeness. Hits were docked into generated TGR 6FMU and 6FMZ ProtoMols and binding affinities calculated. In the de novo approach, DVK was selected as the lead molecule. A 2D topology map guided the modelling of 2 seed structures which were allowed to grow within the TGR ligand binding pocket using LigBuilder v1.2. The outcome was the generation of 2 cohorts of lead-like and Lipinski rule compliant molecules that had in silico affinity for the TGR enzyme. Virtual screening produced a cohort of 1173 molecules each, with the top three molecules having Total Score values of 8.22, 7.83 and 7.86. De novo design using 2 modelled seeds successfully generated a cohort of novel structures, which were evaluated for structural similarity and filtered for Lipinski rule compliance. Both VS and de novo methods have produced molecular cohorts that are structurally varied and show in silico affinity for the TGR enzyme. A sub cohort of molecules from the virtual screening results have been shown to be Ghose, Veber and rule of three compliant. Future efforts should focus on determining the viability of these generated structures as an alternative treatment to schistosomiasis with further validation and in vivo testing.