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

MARTÍNEZ SAYÉ M; MACIEL BJ; GALCERAN F; REIGADA C; RENGIFO M; DI GIROLAMO F; MIRANDA MR; PEREIRA CA

Congreso; XXXII Molecular Parasitology Meeting; 2021

Marine Biological Laboratory, Woods Hole

Trypanosoma cruzi is the causative agent of Chagas disease, which affects almost 7 million peoplemainly 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 argininecan be converted to phosphoarginine through a reversible reaction catalyzed by arginine kinase(AK): arginine + ATP P-arginine + ADP. Overexpression of arginine transporter TcAAP3augments intracellular arginine and induces AK downregulation to compensate the increase inATP consumption suggesting that T. cruzi?s viability can be affected through fluctuations inarginine uptake. Additionally, essentiality of arginine permease TbAAT5 from T. brucei,orthologous to TcAAP3, has been proved through RNAi assays. In this work we identify potentialTcAAP3 inhibitors that may also have trypanocidal effect on T. cruzi. L-arginine was used astemplate molecule in a similarity-based virtual screening applied to 320,000 query compounds,including worldwide approved drugs and natural products among others. After thoroughinspection, 45 compounds were selected for molecular docking assays. Since the 3D structure ofTcAAP3 is not available, we generated and refined a homology-based model using the crystalstructure 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 withthe TcAAP3 models. The final step will be to evaluate in vitro the best compounds as TcAAP3inhibitors and as trypanocidal drugs. New therapies are needed to treat Chagas disease andcomputer-aided strategies allow the rapid identification of drug candidates.