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.

An Overview on Target-Based Drug Design against Kinetoplastid Protozoan Infections: Human African Trypanosomiasis, Chagas Disease and Leishmaniases

“…FDA-approved drugs and food compounds were evaluated as potent DHFR inhibitors and the most prominent were evaluated in vitro. Biological assays pinpointed compound 35 as a novel therapeutic agent against Changas disease [ 94 ].…”

Virtual Screening of FDA-Approved Drugs against Triose Phosphate Isomerase from Entamoeba histolytica and Giardia lamblia Identifies Inhibitors of Their Trophozoite Growth Phase

“…The increment of free available biological data and advances in computational techniques have led to several new ways of virtual screening, that, compared to in vitro evaluation, have become a cheaper and faster alternative to screen drug libraries. Thus, ligand-based and structure-based virtual drug repositioning are widely used today [ 13 , 14 , 15 , 16 , 17 ].…”

Cascade Deep Forest With Heterogeneous Similarity Measures for Drug–Target Interaction Prediction

“…In general, the traditional methods for calculating drug target interactions mainly consist of ligand method and structure method ( Huang et al, 2020 ; Yang et al, 2020 ; Zhang et al, 2020 ). The ligand-based methods predict potential DTI via contrasting candidate ligands with known ligands capable of binding to them, but it does not perform well in the absence of ligand information for potential targets ( Juárez-Saldivar et al, 2020 ). The structure-based method mainly uses the docking simulation technology to predict the potential DTI on the basis of known three-dimensional structure.…”