Discovery of new potent hits against intracellular Trypanosoma cruzi by QSAR-based virtual screening

Cleber C. Melo-Filho, Rodolpho C. Braga, Ievgen Muratov, Caio Haddad Franco, Carolina B. Moraes, Lucio H. Freitas-Junior, Carolina Horta Andrade

Research output: Contribution to journalArticle

Abstract

Chagas disease is a neglected tropical disease (NTD) caused by the protozoan parasite Trypanosoma cruzi and is primarily transmitted to humans by the feces of infected Triatominae insects during their blood meal. The disease affects 6–8 million people, mostly in Latin America countries, and kills more people in the region each year than any other parasite-born disease, including malaria. Moreover, patient numbers are currently increasing in non-endemic, developed countries, such as Australia, Japan, Canada, and the United States. The treatment is limited to one drug, benznidazole, which is only effective in the acute phase of the disease and is very toxic. Thus, there is an urgent need to develop new, safer, and effective drugs against the chronic phase of Chagas disease. Using a QSAR-based virtual screening followed by in vitro experimental evaluation, we report herein the identification of novel potent and selective hits against T. cruzi intracellular stage. We developed and validated binary QSAR models for prediction of anti-trypanosomal activity and cytotoxicity against mammalian cells using the best practices for QSAR modeling. These models were then used for virtual screening of a commercial database, leading to the identification of 39 virtual hits. Further in vitro assays showed that seven compounds were potent against intracellular T. cruzi at submicromolar concentrations (EC50 < 1 μM) and were very selective (SI > 30). Furthermore, other six compounds were also inside the hit criteria for Chagas disease, which presented activity at low micromolar concentrations (EC50 < 10 μM) against intracellular T. cruzi and were also selective (SI > 15). Moreover, we performed a multi-parameter analysis for the comparison of tested compounds regarding their balance between potency, selectivity, and predicted ADMET properties. In the next studies, the most promising compounds will be submitted to additional in vitro and in vivo assays in acute model of Chagas disease, and can be further optimized for the development of new promising drug candidates against this important yet neglected disease.

LanguageEnglish (US)
Pages649-659
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
DOIs
StatePublished - Feb 1 2019

Fingerprint

Quantitative Structure-Activity Relationship
Chagas Disease
Trypanosoma cruzi
Screening
Neglected Diseases
Parasites
Triatominae
Pharmaceutical Preparations
Latin America
Poisons
Acute Disease
Practice Guidelines
Developed Countries
Feces
Malaria
Canada
Insects
Meals
Japan
Assays

Keywords

  • AATNXLRILQHNNJ-UHFFFAOYSA-N
  • ADMET
  • ADURSCIXNLSVQS-UHFFFAOYSA-N
  • AOKMDMGBLJTZGR-UHFFFAOYSA-N
  • BYOLMMOSOOWSCY-UHFFFAOYSA-N
  • CXTFKBZEJHZYLK-UHFFFAOYSA-N
  • Chagas disease
  • DDVVNKRYLQKSGG-UHFFFAOYSA-N
  • DRTFDDDOEPZMBV-UHFFFAOYSA-N
  • DXFMQYJFEFGUOP-UHFFFAOYSA-N
  • FPGVBDJFGIPBOP-UHFFFAOYSA-N
  • GEKWYGVEXDUQMM-YBFXNURJSA-N
  • GVDVCLSVHXYYLI-UHFFFAOYSA-N
  • GZLOHJDOCVFGGT-UHFFFAOYSA-N
  • HFGPYNFXBGMMSA-UHFFFAOYSA-N
  • HRXHGCHJYURSOR-UHFFFAOYSA-N
  • HTCCIUHRGFQLQN-UHFFFAOYSA-N
  • High content screening
  • IDFBBTXKWWRWRE-UHFFFAOYSA-N
  • IFKWKGQLVLTMRK-UHFFFAOYSA-N
  • INFUOHFIFLJRQU-UHFFFAOYSA-N
  • JGTKOGPGZTZRHR-UHFFFAOYSA-N
  • JJCWPJGSCGYDJY-UHFFFAOYSA-N
  • KCFFGQZFWUERFK-UHFFFAOYSA-N
  • MNTNUJRSUUCIQU-UHFFFAOYSA-N
  • NOYMFFNOKLQSBC-UHFFFAOYSA-N
  • OMGYDFJDQNSOID-UHFFFAOYSA-N
  • PVNVQDOMOBPOJT-UHFFFAOYSA-N
  • QSAR
  • QSIMVHYUETVKLU-UHFFFAOYSA-N
  • RFAFVASFJZRVSO-UHFFFAOYSA-N
  • RWVBBRPYWDKZHZ-UHFFFAOYSA-N
  • SQRZBVGHYBLYAV-UHFFFAOYSA-N
  • SYSNWVRIFFGJMH-IYLWIWFWSA-N
  • TWQKFBMUPUVCBS-UHFFFAOYSA-N
  • Validated hits
  • Virtual screening
  • WYPKEYYHHGXWMF-UHFFFAOYSA-N
  • XIHFGQFLZWWLPW-UHFFFAOYSA-N
  • XOPJDZYCKZQCOE-UHFFFAOYSA-N
  • YDUBFYIHZUAMSD-UHFFFAOYSA-N
  • YWJZRAHEPABBHR-UHFFFAOYSA-N
  • YZFKPFBMODFUJJ-UHFFFAOYSA-N
  • ZSGOAOORBZJWLL-UHFFFAOYSA-N
  • ZWIWAKSDZPSANW-UHFFFAOYSA-N

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Discovery of new potent hits against intracellular Trypanosoma cruzi by QSAR-based virtual screening. / Melo-Filho, Cleber C.; Braga, Rodolpho C.; Muratov, Ievgen; Franco, Caio Haddad; Moraes, Carolina B.; Freitas-Junior, Lucio H.; Andrade, Carolina Horta.

In: European Journal of Medicinal Chemistry, 01.02.2019, p. 649-659.

Research output: Contribution to journalArticle

Melo-Filho, Cleber C. ; Braga, Rodolpho C. ; Muratov, Ievgen ; Franco, Caio Haddad ; Moraes, Carolina B. ; Freitas-Junior, Lucio H. ; Andrade, Carolina Horta. / Discovery of new potent hits against intracellular Trypanosoma cruzi by QSAR-based virtual screening. In: European Journal of Medicinal Chemistry. 2019 ; pp. 649-659.
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AU - Melo-Filho, Cleber C.

AU - Braga, Rodolpho C.

AU - Muratov, Ievgen

AU - Franco, Caio Haddad

AU - Moraes, Carolina B.

AU - Freitas-Junior, Lucio H.

AU - Andrade, Carolina Horta

PY - 2019/2/1

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N2 - Chagas disease is a neglected tropical disease (NTD) caused by the protozoan parasite Trypanosoma cruzi and is primarily transmitted to humans by the feces of infected Triatominae insects during their blood meal. The disease affects 6–8 million people, mostly in Latin America countries, and kills more people in the region each year than any other parasite-born disease, including malaria. Moreover, patient numbers are currently increasing in non-endemic, developed countries, such as Australia, Japan, Canada, and the United States. The treatment is limited to one drug, benznidazole, which is only effective in the acute phase of the disease and is very toxic. Thus, there is an urgent need to develop new, safer, and effective drugs against the chronic phase of Chagas disease. Using a QSAR-based virtual screening followed by in vitro experimental evaluation, we report herein the identification of novel potent and selective hits against T. cruzi intracellular stage. We developed and validated binary QSAR models for prediction of anti-trypanosomal activity and cytotoxicity against mammalian cells using the best practices for QSAR modeling. These models were then used for virtual screening of a commercial database, leading to the identification of 39 virtual hits. Further in vitro assays showed that seven compounds were potent against intracellular T. cruzi at submicromolar concentrations (EC50 < 1 μM) and were very selective (SI > 30). Furthermore, other six compounds were also inside the hit criteria for Chagas disease, which presented activity at low micromolar concentrations (EC50 < 10 μM) against intracellular T. cruzi and were also selective (SI > 15). Moreover, we performed a multi-parameter analysis for the comparison of tested compounds regarding their balance between potency, selectivity, and predicted ADMET properties. In the next studies, the most promising compounds will be submitted to additional in vitro and in vivo assays in acute model of Chagas disease, and can be further optimized for the development of new promising drug candidates against this important yet neglected disease.

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