Repositioned Drugs for Chagas Disease Unveiled via Structure-Based Drug Repositioning

Abstract

Chagas disease, caused by the parasite Trypanosoma cruzi, affects millions of people in South America. The current treatments are limited, have severe side effects, and are only partially effective. Drug repositioning, defined as finding new indications for already approved drugs, has the potential to provide new therapeutic options for Chagas. In this work, we conducted a structure-based drug repositioning approach with over 130,000 3D protein structures to identify drugs that bind therapeutic Chagas targets and thus represent potential new Chagas treatments. The screening yielded over 500 molecules as hits, out of which 38 drugs were prioritized following a rigorous filtering process. About half of the latter were already known to have trypanocidal activity, while the others are novel to Chagas disease. Three of the new drug candidates—ciprofloxacin, naproxen, and folic acid—showed a growth inhibitory activity in the micromolar range when tested ex vivo on T. cruzi trypomastigotes, validating the prediction. We show that our drug repositioning approach is able to pinpoint relevant drug candidates at a fraction of the time and cost of a conventional screening. Furthermore, our results demonstrate the power and potential of structure-based drug repositioning in the context of neglected tropical diseases where the pharmaceutical industry has little financial interest in the development of new drugs.

Structural binding site comparisons reveal Crizotinib as a novel LRRK2 inhibitor

“…Still, as a screening approach, our structure-based method has very high success rates. In previous studies, the approach demonstrated to predict 5–10% binders [63] , [29] , [18] , which is superior to high-throughput screenings. In the present study, two out of six hit compounds actually bind LRRK2 G2019S, which corresponds to a success rate of 33%.…”

“…An interaction feature was defined by the combination of two non-covalent interactions within an angle and distance range. If a particular interaction feature was present in the interaction pattern, the respective bin was set to 1, otherwise, it was set to 0, as already described in [29] , [18] . The interaction fingerprints are available from PharmAI (Dresden, Germany).…”

“…The exponential growth of structural data [14] and recent progress in protein structure prediction [15] , [16] make structure-based methods a promising approach to this strategy [17] . As a prime example, we recently identified three potent, inexpensive, and easily available drug repositioning candidates for Chagas disease by comparing protein–ligand interaction profiles of Chagas targets and other proteins [18] .…”

The Trypanosoma cruzi kinetoplast DNA minicircle sequences transfer biomarker of the multidrug treatment of Chagas disease

“…To approaching the multidrug treatment of the T. cruzi infections we selected the polymerases inhibitor 4-Fluorquinolone Ofloxacin [136–137] and the Azidothymidine reverse transcriptase inhibitor [114, 115], and the lead nitro heterocycle Benznidazole. The treatment of the acutely T. cruzi- infected BALB/c mice with the Benznidazole curtailed the parasitemia at the 15 th day of the drug administration, whereas the flagellates lasted for 40 days in the blood of the infected-untreated mice.…”

“…Campthothecin Inhibits PP1 and PP2 at serine/threonine phosphatases and cell growth inhibition 50 [129,130] Cycloheximide Inhibits p38 activated protein kinase (MAKPK) a nd cell entry at G2/M phase 5 [131,132] Etoposide Down regulate polymerase II at S-G2 phases and prevents cell division 50 [133,134] Ofloxacin 4-Fluorquinolone inhibits polymerase at G2/M phase, and apoptosis 30 [135,136] Praziquantel Isoquinolone inhibits serine/threonine kinase (PI3-k) polymerases I and II 46 [137][138][139] Staurosporine Protein kinases inhibitor (A, C, CAM and PI3K) prevents cell growth at G1 check point 9 [140,141] *Each drug suspension (µg/100 µL) in 0.15M NaCl used in the cytotoxic in vitro assays. µg…”