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Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design
Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was perf...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309560/ https://www.ncbi.nlm.nih.gov/pubmed/25629509 http://dx.doi.org/10.1371/journal.pone.0113705 |
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author | Fjellström, Ola Akkaya, Sibel Beisel, Hans-Georg Eriksson, Per-Olof Erixon, Karl Gustafsson, David Jurva, Ulrik Kang, Daiwu Karis, David Knecht, Wolfgang Nerme, Viveca Nilsson, Ingemar Olsson, Thomas Redzic, Alma Roth, Robert Sandmark, Jenny Tigerström, Anna Öster, Linda |
author_facet | Fjellström, Ola Akkaya, Sibel Beisel, Hans-Georg Eriksson, Per-Olof Erixon, Karl Gustafsson, David Jurva, Ulrik Kang, Daiwu Karis, David Knecht, Wolfgang Nerme, Viveca Nilsson, Ingemar Olsson, Thomas Redzic, Alma Roth, Robert Sandmark, Jenny Tigerström, Anna Öster, Linda |
author_sort | Fjellström, Ola |
collection | PubMed |
description | Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1’-S2’ FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1’-S2’ binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC(50) of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1’-S2’ binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds. |
format | Online Article Text |
id | pubmed-4309560 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-43095602015-02-06 Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design Fjellström, Ola Akkaya, Sibel Beisel, Hans-Georg Eriksson, Per-Olof Erixon, Karl Gustafsson, David Jurva, Ulrik Kang, Daiwu Karis, David Knecht, Wolfgang Nerme, Viveca Nilsson, Ingemar Olsson, Thomas Redzic, Alma Roth, Robert Sandmark, Jenny Tigerström, Anna Öster, Linda PLoS One Research Article Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1’-S2’ FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1’-S2’ binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC(50) of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1’-S2’ binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds. Public Library of Science 2015-01-28 /pmc/articles/PMC4309560/ /pubmed/25629509 http://dx.doi.org/10.1371/journal.pone.0113705 Text en © 2015 Fjellström et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Fjellström, Ola Akkaya, Sibel Beisel, Hans-Georg Eriksson, Per-Olof Erixon, Karl Gustafsson, David Jurva, Ulrik Kang, Daiwu Karis, David Knecht, Wolfgang Nerme, Viveca Nilsson, Ingemar Olsson, Thomas Redzic, Alma Roth, Robert Sandmark, Jenny Tigerström, Anna Öster, Linda Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design |
title | Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design |
title_full | Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design |
title_fullStr | Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design |
title_full_unstemmed | Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design |
title_short | Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design |
title_sort | creating novel activated factor xi inhibitors through fragment based lead generation and structure aided drug design |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309560/ https://www.ncbi.nlm.nih.gov/pubmed/25629509 http://dx.doi.org/10.1371/journal.pone.0113705 |
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