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Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist atta...

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Autores principales: Botelho, Fernanda D., dos Santos, Marcelo C., Gonçalves, Arlan da S., Kuca, Kamil, Valis, Martin, LaPlante, Steven R., França, Tanos C. C., de Almeida, Joyce S. F. D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761309/
https://www.ncbi.nlm.nih.gov/pubmed/33256167
http://dx.doi.org/10.3390/toxins12120746
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author Botelho, Fernanda D.
dos Santos, Marcelo C.
Gonçalves, Arlan da S.
Kuca, Kamil
Valis, Martin
LaPlante, Steven R.
França, Tanos C. C.
de Almeida, Joyce S. F. D.
author_facet Botelho, Fernanda D.
dos Santos, Marcelo C.
Gonçalves, Arlan da S.
Kuca, Kamil
Valis, Martin
LaPlante, Steven R.
França, Tanos C. C.
de Almeida, Joyce S. F. D.
author_sort Botelho, Fernanda D.
collection PubMed
description Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.
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spelling pubmed-77613092020-12-26 Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors Botelho, Fernanda D. dos Santos, Marcelo C. Gonçalves, Arlan da S. Kuca, Kamil Valis, Martin LaPlante, Steven R. França, Tanos C. C. de Almeida, Joyce S. F. D. Toxins (Basel) Article Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation. MDPI 2020-11-26 /pmc/articles/PMC7761309/ /pubmed/33256167 http://dx.doi.org/10.3390/toxins12120746 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Botelho, Fernanda D.
dos Santos, Marcelo C.
Gonçalves, Arlan da S.
Kuca, Kamil
Valis, Martin
LaPlante, Steven R.
França, Tanos C. C.
de Almeida, Joyce S. F. D.
Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors
title Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors
title_full Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors
title_fullStr Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors
title_full_unstemmed Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors
title_short Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors
title_sort ligand-based virtual screening, molecular docking, molecular dynamics, and mm-pbsa calculations towards the identification of potential novel ricin inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761309/
https://www.ncbi.nlm.nih.gov/pubmed/33256167
http://dx.doi.org/10.3390/toxins12120746
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