Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling

Area of Science:

• Parasitology
• Drug Discovery
• Computational Chemistry

Background:

• Chagas disease affects millions globally, with limited and problematic treatment options.
• The enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) from Trypanosoma cruzi (T. cruzi) is a key drug target.
• Existing treatments for Chagas disease have limitations including side effects and drug resistance.

Purpose of the Study:

• To identify novel drug repositioning opportunities for Chagas disease treatment.
• To discover new inhibitors of the T. cruzi DHFR-TS enzyme.
• To develop improved therapeutic strategies against T. cruzi infection.

Main Methods:

• A novel virtual screening approach combining docking and protein-ligand interaction profiling.
• Screening of FDA-approved drugs for potential binding to T. cruzi DHFR-TS.
• In vitro testing of identified compounds against T. cruzi epimastigotes.

Main Results:

• Ten potential T. cruzi DHFR-TS inhibitors were identified through virtual screening.
• Selected compounds demonstrated conserved molecular interactions and higher binding affinity than trimetrexate.
• Nilotinib, glipizide, glyburide, and gliquidone showed growth inhibitory activity against T. cruzi epimastigotes.

Conclusions:

• The identified FDA-approved drugs represent promising candidates for new Chagas disease treatments.
• This virtual screening approach effectively identified potential drug repositioning opportunities.
• Further development of these compounds could lead to improved therapies for Chagas disease.