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Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches
Factor Xa (FXa), a vitamin K-dependent serine protease plays a pivotal role in the coagulation cascade, one of the most interesting targets for the development of new anticoagulants. In the present work, we performed a virtual screening campaign based on ligand-based shape and electrostatic similari...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151700/ https://www.ncbi.nlm.nih.gov/pubmed/28937618 http://dx.doi.org/10.3390/molecules22101588 |
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author | Lagos, Carlos F. Segovia, Gerardine F. Nuñez-Navarro, Nicolás Faúndez, Mario A. Zacconi, Flavia C. |
author_facet | Lagos, Carlos F. Segovia, Gerardine F. Nuñez-Navarro, Nicolás Faúndez, Mario A. Zacconi, Flavia C. |
author_sort | Lagos, Carlos F. |
collection | PubMed |
description | Factor Xa (FXa), a vitamin K-dependent serine protease plays a pivotal role in the coagulation cascade, one of the most interesting targets for the development of new anticoagulants. In the present work, we performed a virtual screening campaign based on ligand-based shape and electrostatic similarity search and protein-ligand docking to discover novel FXa-targeted scaffolds for further development of inhibitors. From an initial set of 260,000 compounds from the NCI Open database, 30 potential FXa inhibitors were identified and selected for in vitro biological evaluation. Compound 5 (NSC635393, 4-(3-methyl-4H-1,4-benzothiazin-2-yl)-2,4-dioxo-N-phenylbutanamide) displayed an IC(50) value of 2.02 nM against human FXa. The identified compound may serve as starting point for the development of novel FXa inhibitors. |
format | Online Article Text |
id | pubmed-6151700 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-61517002018-11-13 Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches Lagos, Carlos F. Segovia, Gerardine F. Nuñez-Navarro, Nicolás Faúndez, Mario A. Zacconi, Flavia C. Molecules Article Factor Xa (FXa), a vitamin K-dependent serine protease plays a pivotal role in the coagulation cascade, one of the most interesting targets for the development of new anticoagulants. In the present work, we performed a virtual screening campaign based on ligand-based shape and electrostatic similarity search and protein-ligand docking to discover novel FXa-targeted scaffolds for further development of inhibitors. From an initial set of 260,000 compounds from the NCI Open database, 30 potential FXa inhibitors were identified and selected for in vitro biological evaluation. Compound 5 (NSC635393, 4-(3-methyl-4H-1,4-benzothiazin-2-yl)-2,4-dioxo-N-phenylbutanamide) displayed an IC(50) value of 2.02 nM against human FXa. The identified compound may serve as starting point for the development of novel FXa inhibitors. MDPI 2017-09-22 /pmc/articles/PMC6151700/ /pubmed/28937618 http://dx.doi.org/10.3390/molecules22101588 Text en © 2017 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 Lagos, Carlos F. Segovia, Gerardine F. Nuñez-Navarro, Nicolás Faúndez, Mario A. Zacconi, Flavia C. Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches |
title | Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches |
title_full | Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches |
title_fullStr | Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches |
title_full_unstemmed | Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches |
title_short | Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches |
title_sort | novel fxa inhibitor identification through integration of ligand- and structure-based approaches |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151700/ https://www.ncbi.nlm.nih.gov/pubmed/28937618 http://dx.doi.org/10.3390/molecules22101588 |
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