In silico identification of new inhibitors of the arginine transporter TcAAP3 from Trypanosoma cruzi

SAYE, MELISA; MACIEL, BELEN; GALCERAN, FACUNDO; REIGADA, CHANTAL; RENGIFO, MARCOS; DIGIROLAMO FABIO; MIRANDA, MARIANA; PEREIRA, CA

Congreso; Molecular Parasitology Meeting XXII; 2021

Marine biological laboratory

Trypanosoma cruzi is the causative agent of Chagas disease, which affects almost 7 million people mainly in Latin America. The parasite metabolism is widely based on amino acid consumption, both as alternative carbon and energy sources and as energy reservoirs. The amino acid arginine can be converted to phosphoarginine through a reversible reaction catalyzed by arginine kinase (AK): arginine + ATP P-arginine + ADP. Overexpression of arginine transporter TcAAP3 augments intracellular arginine and induces AK downregulation to compensate the increase in ATP consumption suggesting that T. cruzi’s viability can be affected through fluctuations in arginine uptake. Additionally, essentiality of arginine permease TbAAT5 from T. brucei, orthologous to TcAAP3, has been proved through RNAi assays. In this work we identify potential TcAAP3 inhibitors that may also have trypanocidal effect on T. cruzi. L-arginine was used as template molecule in a similarity-based virtual screening applied to 320,000 query compounds, including worldwide approved drugs and natural products among others. After thorough inspection, 45 compounds were selected for molecular docking assays. Since the 3D structure of TcAAP3 is not available, we generated and refined a homology-based model using the crystal structure of the neutral amino acid transporter SLC38A9 (PDB 7KGV) as template. Next, molecular docking assays were performed to predict the binding of the potential inhibitors with the TcAAP3 models. The final step will be to evaluate in vitro the best compounds as TcAAP3 inhibitors and as trypanocidal drugs. New therapies are needed to treat Chagas disease and computer-aided strategies allow the rapid identification of drug candidates.