Identification of new inhibitors of the arginine transporter TcAAP3 from Trypanosoma cruzi through an in silico strategy

MELISA M SAYÉ; CHANTAL REIGADA; DI GIROLAMO, FABIO AUGUSTO; CLAUDIO A PEREIRA

Conferencia; NTD Network Early Career Researcher Conference 2022; 2022

In this work we identify potential TcAAP3 inhibitors that may alsohave trypanocidal effect on T. cruzi. L-arginine was used astemplate molecule in a similarity-based virtual screening applied to320,000 query compounds, including worldwide approved drugsand natural products among others. After thorough inspection, 45compounds were selected for molecular docking assays. Since the3D structure of the arginine transporter TcAAP3 is not available, wegenerated and refined a homology-based model using the crystalstructure of the neutral amino acid transporter SLC38A9 (PDB7KGV) as template. Next, molecular docking assays wereperformed to predict the binding of the potential inhibitors with theTcAAP3 model. From these results, 5 compounds were selected forin vitro assays, and are currently under evaluation as TcAAP3inhibitors and as trypanocidal drugs. The 5 compounds selected areiobenguane, sulfaguanidine, isotretinoin, assymetricdimethylarginine and aminohippuric acid. Using a similar approachwe have identified inhibitors of the proline and the polyaminestransporters TcAAAP069 and TcPAT12 with trypanocidal action.New therapies are needed to treat Chagas disease and computer-aided strategies allow the rapid identification of drug candidates.