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

Abstract

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment. Bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) has emerged as a promising pharmacological target. Moreover, some human dihydrofolate reductase (HsDHFR) inhibitors such as trimetrexate also inhibit T. cruzi DHFR-TS (TcDHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for new TcDHFR-TS inhibitors. In this paper, a novel virtual screening approach was developed that combines classical docking with protein-ligand interaction profiling to identify drug repositioning opportunities against T. cruzi infection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity to TcDHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putative TcDHFR-TS inhibitors were identified. These exhibited a similar interaction profile and a higher computed binding affinity, compared to trimetrexate. Nilotinib, glipizide, glyburide and gliquidone were tested on T. cruzi epimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease.

• Authors: Alfredo Juárez-Saldivar, Michael Schroeder, Sebastian Salentin, V Joachim Haupt, Emma Saavedra, Citlali Vázquez, Francisco Reyes-Espinosa, Verónica Herrera-Mayorga, Juan Carlos Villalobos-Rocha, Carlos A García-Pérez, Nuria E Campillo, Gildardo Rivera
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 12 (Jun 16 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32560043 (Publication Type: Journal Article)

Chemical References

• Folic Acid Antagonists
• Ligands
• Pyrimidines
• Sulfonylurea Compounds
• Trypanocidal Agents
• gliquidone
• nilotinib
• Glyburide
• Glipizide

Topics

• Chagas Disease (drug therapy, enzymology)
• Computer Simulation
• Drug Repositioning
• Folic Acid Antagonists (chemistry, pharmacology)
• Glipizide (chemistry, pharmacology)
• Glyburide (chemistry, pharmacology)
• Humans
• Ligands
• Molecular Docking Simulation
• Molecular Structure
• Pyrimidines (chemistry, pharmacology)
• Structure-Activity Relationship
• Sulfonylurea Compounds (chemistry, pharmacology)
• Trypanocidal Agents (chemistry, pharmacology)
• Trypanosoma cruzi (drug effects)