Structure-based virtual screening and in vitro evaluation of new trypanosoma cruzi cruzain inhibitors

Verónica Herrera-Mayorga, Edgar E. Lara-Ramírez, Karla F. Chacón-Vargas, Charmina Aguirre-Alvarado, Lorena Rodríguez-Páez, Verónica Alcántara-Farfán, Joaquín Cordero-Martínez, Benjamín Nogueda-Torres, Francisco Reyes-Espinosa, Virgilio Bocanegra-García, Gildardo Rivera

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2 Citations (Scopus)

Abstract

Chagas disease (CD), or American trypanosomiasis, causes more than 10,000 deaths per year in the Americas. Current medical therapy for CD has low efficacy in the chronic phase of the disease and serious adverse effects; therefore, it is necessary to search for new pharmacological treatments. In this work, the ZINC15 database was filtered using the N-acylhydrazone moiety and a subsequent structure-based virtual screening was performed using the cruzain enzyme of Trypanosoma cruzi to predict new potential cruzain inhibitors. After a rational selection process, four compounds, Z2 (ZINC9873043), Z3 (ZINC9870651), Z5 (ZINC9715287), and Z6 (ZINC9861447), were chosen to evaluate their in vitro trypanocidal activity and enzyme inhibition. Compound Z5 showed the best trypanocidal activity against epimatigote (IC50 = 36.26 ± 9.9 µM) and trypomastigote (IC50 = 166.21 ± 14.5 µM and 185.1 ± 8.5 µM on NINOA and INC-5 strains, respectively) forms of Trypanosoma cruzi. In addition, Z5 showed a better inhibitory effect on Trypanosoma cruzi proteases than S1 (STK552090, 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]-indol-4-amine), a known cruzain inhibitor. This study encourages the use of computational tools for the rational search for trypanocidal drugs.

Original languageEnglish
Article number1742
JournalInternational Journal of Molecular Sciences
Volume20
Issue number7
DOIs
StatePublished - 1 Apr 2019

Fingerprint

Chagas Disease
inhibitors
Screening
screening
Trypanosoma cruzi
Inhibitory Concentration 50
enzymes
evaluation
Trypanocidal Agents
Enzyme inhibition
protease
Enzymes
death
Amines
therapy
amines
drugs
Peptide Hydrolases
Chronic Disease
Databases

Keywords

  • Cruzain
  • Inhibitors
  • Molecular docking
  • Trypanosoma cruzi
  • Zinc

Cite this

@article{aa6190b84ea84e08a728dedadbe56c61,
title = "Structure-based virtual screening and in vitro evaluation of new trypanosoma cruzi cruzain inhibitors",
abstract = "Chagas disease (CD), or American trypanosomiasis, causes more than 10,000 deaths per year in the Americas. Current medical therapy for CD has low efficacy in the chronic phase of the disease and serious adverse effects; therefore, it is necessary to search for new pharmacological treatments. In this work, the ZINC15 database was filtered using the N-acylhydrazone moiety and a subsequent structure-based virtual screening was performed using the cruzain enzyme of Trypanosoma cruzi to predict new potential cruzain inhibitors. After a rational selection process, four compounds, Z2 (ZINC9873043), Z3 (ZINC9870651), Z5 (ZINC9715287), and Z6 (ZINC9861447), were chosen to evaluate their in vitro trypanocidal activity and enzyme inhibition. Compound Z5 showed the best trypanocidal activity against epimatigote (IC50 = 36.26 ± 9.9 µM) and trypomastigote (IC50 = 166.21 ± 14.5 µM and 185.1 ± 8.5 µM on NINOA and INC-5 strains, respectively) forms of Trypanosoma cruzi. In addition, Z5 showed a better inhibitory effect on Trypanosoma cruzi proteases than S1 (STK552090, 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]-indol-4-amine), a known cruzain inhibitor. This study encourages the use of computational tools for the rational search for trypanocidal drugs.",
keywords = "Cruzain, Inhibitors, Molecular docking, Trypanosoma cruzi, Zinc",
author = "Ver{\'o}nica Herrera-Mayorga and Lara-Ram{\'i}rez, {Edgar E.} and Chac{\'o}n-Vargas, {Karla F.} and Charmina Aguirre-Alvarado and Lorena Rodr{\'i}guez-P{\'a}ez and Ver{\'o}nica Alc{\'a}ntara-Farf{\'a}n and Joaqu{\'i}n Cordero-Mart{\'i}nez and Benjam{\'i}n Nogueda-Torres and Francisco Reyes-Espinosa and Virgilio Bocanegra-Garc{\'i}a and Gildardo Rivera",
year = "2019",
month = "4",
day = "1",
doi = "10.3390/ijms20071742",
language = "Ingl{\'e}s",
volume = "20",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "7",

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TY - JOUR

T1 - Structure-based virtual screening and in vitro evaluation of new trypanosoma cruzi cruzain inhibitors

AU - Herrera-Mayorga, Verónica

AU - Lara-Ramírez, Edgar E.

AU - Chacón-Vargas, Karla F.

AU - Aguirre-Alvarado, Charmina

AU - Rodríguez-Páez, Lorena

AU - Alcántara-Farfán, Verónica

AU - Cordero-Martínez, Joaquín

AU - Nogueda-Torres, Benjamín

AU - Reyes-Espinosa, Francisco

AU - Bocanegra-García, Virgilio

AU - Rivera, Gildardo

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Chagas disease (CD), or American trypanosomiasis, causes more than 10,000 deaths per year in the Americas. Current medical therapy for CD has low efficacy in the chronic phase of the disease and serious adverse effects; therefore, it is necessary to search for new pharmacological treatments. In this work, the ZINC15 database was filtered using the N-acylhydrazone moiety and a subsequent structure-based virtual screening was performed using the cruzain enzyme of Trypanosoma cruzi to predict new potential cruzain inhibitors. After a rational selection process, four compounds, Z2 (ZINC9873043), Z3 (ZINC9870651), Z5 (ZINC9715287), and Z6 (ZINC9861447), were chosen to evaluate their in vitro trypanocidal activity and enzyme inhibition. Compound Z5 showed the best trypanocidal activity against epimatigote (IC50 = 36.26 ± 9.9 µM) and trypomastigote (IC50 = 166.21 ± 14.5 µM and 185.1 ± 8.5 µM on NINOA and INC-5 strains, respectively) forms of Trypanosoma cruzi. In addition, Z5 showed a better inhibitory effect on Trypanosoma cruzi proteases than S1 (STK552090, 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]-indol-4-amine), a known cruzain inhibitor. This study encourages the use of computational tools for the rational search for trypanocidal drugs.

AB - Chagas disease (CD), or American trypanosomiasis, causes more than 10,000 deaths per year in the Americas. Current medical therapy for CD has low efficacy in the chronic phase of the disease and serious adverse effects; therefore, it is necessary to search for new pharmacological treatments. In this work, the ZINC15 database was filtered using the N-acylhydrazone moiety and a subsequent structure-based virtual screening was performed using the cruzain enzyme of Trypanosoma cruzi to predict new potential cruzain inhibitors. After a rational selection process, four compounds, Z2 (ZINC9873043), Z3 (ZINC9870651), Z5 (ZINC9715287), and Z6 (ZINC9861447), were chosen to evaluate their in vitro trypanocidal activity and enzyme inhibition. Compound Z5 showed the best trypanocidal activity against epimatigote (IC50 = 36.26 ± 9.9 µM) and trypomastigote (IC50 = 166.21 ± 14.5 µM and 185.1 ± 8.5 µM on NINOA and INC-5 strains, respectively) forms of Trypanosoma cruzi. In addition, Z5 showed a better inhibitory effect on Trypanosoma cruzi proteases than S1 (STK552090, 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]-indol-4-amine), a known cruzain inhibitor. This study encourages the use of computational tools for the rational search for trypanocidal drugs.

KW - Cruzain

KW - Inhibitors

KW - Molecular docking

KW - Trypanosoma cruzi

KW - Zinc

UR - http://www.scopus.com/inward/record.url?scp=85064722845&partnerID=8YFLogxK

U2 - 10.3390/ijms20071742

DO - 10.3390/ijms20071742

M3 - Artículo

C2 - 30970549

AN - SCOPUS:85064722845

VL - 20

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 7

M1 - 1742

ER -