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Docking-Based Virtual Screening Enables Prioritizing Protein Kinase Inhibitors With In Vitro Phenotypic Activity Against Schistosoma mansoni

Schistosomiasis is a parasitic neglected disease with praziquantel (PZQ) utilized as the main drug for treatment, despite its low effectiveness against early stages of the worm. To aid in the search for new drugs to tackle schistosomiasis, computer-aided drug design has been proved a helpful tool to...

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Autores principales: Moreira, Bernardo Pereira, Batista, Izabella Cristina Andrade, Tavares, Naiara Clemente, Armstrong, Tom, Gava, Sandra Grossi, Torres, Gabriella Parreiras, Mourão, Marina Moraes, Falcone, Franco H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294739/
https://www.ncbi.nlm.nih.gov/pubmed/35865824
http://dx.doi.org/10.3389/fcimb.2022.913301
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author Moreira, Bernardo Pereira
Batista, Izabella Cristina Andrade
Tavares, Naiara Clemente
Armstrong, Tom
Gava, Sandra Grossi
Torres, Gabriella Parreiras
Mourão, Marina Moraes
Falcone, Franco H.
author_facet Moreira, Bernardo Pereira
Batista, Izabella Cristina Andrade
Tavares, Naiara Clemente
Armstrong, Tom
Gava, Sandra Grossi
Torres, Gabriella Parreiras
Mourão, Marina Moraes
Falcone, Franco H.
author_sort Moreira, Bernardo Pereira
collection PubMed
description Schistosomiasis is a parasitic neglected disease with praziquantel (PZQ) utilized as the main drug for treatment, despite its low effectiveness against early stages of the worm. To aid in the search for new drugs to tackle schistosomiasis, computer-aided drug design has been proved a helpful tool to enhance the search and initial identification of schistosomicidal compounds, allowing fast and cost-efficient progress in drug discovery. The combination of high-throughput in silico data followed by in vitro phenotypic screening assays allows the assessment of a vast library of compounds with the potential to inhibit a single or even several biological targets in a more time- and cost-saving manner. Here, we describe the molecular docking for in silico screening of predicted homology models of five protein kinases (JNK, p38, ERK1, ERK2, and FES) of Schistosoma mansoni against approximately 85,000 molecules from the Managed Chemical Compounds Collection (MCCC) of the University of Nottingham (UK). We selected 169 molecules predicted to bind to SmERK1, SmERK2, SmFES, SmJNK, and/or Smp38 for in vitro screening assays using schistosomula and adult worms. In total, 89 (52.6%) molecules were considered active in at least one of the assays. This approach shows a much higher efficiency when compared to using only traditional high-throughput in vitro screening assays, where initial positive hits are retrieved from testing thousands of molecules. Additionally, when we focused on compound promiscuity over selectivity, we were able to efficiently detect active compounds that are predicted to target all kinases at the same time. This approach reinforces the concept of polypharmacology aiming for “one drug-multiple targets”. Moreover, at least 17 active compounds presented satisfactory drug-like properties score when compared to PZQ, which allows for optimization before further in vivo screening assays. In conclusion, our data support the use of computer-aided drug design methodologies in conjunction with high-throughput screening approach.
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spelling pubmed-92947392022-07-20 Docking-Based Virtual Screening Enables Prioritizing Protein Kinase Inhibitors With In Vitro Phenotypic Activity Against Schistosoma mansoni Moreira, Bernardo Pereira Batista, Izabella Cristina Andrade Tavares, Naiara Clemente Armstrong, Tom Gava, Sandra Grossi Torres, Gabriella Parreiras Mourão, Marina Moraes Falcone, Franco H. Front Cell Infect Microbiol Cellular and Infection Microbiology Schistosomiasis is a parasitic neglected disease with praziquantel (PZQ) utilized as the main drug for treatment, despite its low effectiveness against early stages of the worm. To aid in the search for new drugs to tackle schistosomiasis, computer-aided drug design has been proved a helpful tool to enhance the search and initial identification of schistosomicidal compounds, allowing fast and cost-efficient progress in drug discovery. The combination of high-throughput in silico data followed by in vitro phenotypic screening assays allows the assessment of a vast library of compounds with the potential to inhibit a single or even several biological targets in a more time- and cost-saving manner. Here, we describe the molecular docking for in silico screening of predicted homology models of five protein kinases (JNK, p38, ERK1, ERK2, and FES) of Schistosoma mansoni against approximately 85,000 molecules from the Managed Chemical Compounds Collection (MCCC) of the University of Nottingham (UK). We selected 169 molecules predicted to bind to SmERK1, SmERK2, SmFES, SmJNK, and/or Smp38 for in vitro screening assays using schistosomula and adult worms. In total, 89 (52.6%) molecules were considered active in at least one of the assays. This approach shows a much higher efficiency when compared to using only traditional high-throughput in vitro screening assays, where initial positive hits are retrieved from testing thousands of molecules. Additionally, when we focused on compound promiscuity over selectivity, we were able to efficiently detect active compounds that are predicted to target all kinases at the same time. This approach reinforces the concept of polypharmacology aiming for “one drug-multiple targets”. Moreover, at least 17 active compounds presented satisfactory drug-like properties score when compared to PZQ, which allows for optimization before further in vivo screening assays. In conclusion, our data support the use of computer-aided drug design methodologies in conjunction with high-throughput screening approach. Frontiers Media S.A. 2022-07-05 /pmc/articles/PMC9294739/ /pubmed/35865824 http://dx.doi.org/10.3389/fcimb.2022.913301 Text en Copyright © 2022 Moreira, Batista, Tavares, Armstrong, Gava, Torres, Mourão and Falcone https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
Moreira, Bernardo Pereira
Batista, Izabella Cristina Andrade
Tavares, Naiara Clemente
Armstrong, Tom
Gava, Sandra Grossi
Torres, Gabriella Parreiras
Mourão, Marina Moraes
Falcone, Franco H.
Docking-Based Virtual Screening Enables Prioritizing Protein Kinase Inhibitors With In Vitro Phenotypic Activity Against Schistosoma mansoni
title Docking-Based Virtual Screening Enables Prioritizing Protein Kinase Inhibitors With In Vitro Phenotypic Activity Against Schistosoma mansoni
title_full Docking-Based Virtual Screening Enables Prioritizing Protein Kinase Inhibitors With In Vitro Phenotypic Activity Against Schistosoma mansoni
title_fullStr Docking-Based Virtual Screening Enables Prioritizing Protein Kinase Inhibitors With In Vitro Phenotypic Activity Against Schistosoma mansoni
title_full_unstemmed Docking-Based Virtual Screening Enables Prioritizing Protein Kinase Inhibitors With In Vitro Phenotypic Activity Against Schistosoma mansoni
title_short Docking-Based Virtual Screening Enables Prioritizing Protein Kinase Inhibitors With In Vitro Phenotypic Activity Against Schistosoma mansoni
title_sort docking-based virtual screening enables prioritizing protein kinase inhibitors with in vitro phenotypic activity against schistosoma mansoni
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294739/
https://www.ncbi.nlm.nih.gov/pubmed/35865824
http://dx.doi.org/10.3389/fcimb.2022.913301
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