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X-ray-Structure-Based Identification of Compounds with Activity against Targets from Different Families and Generation of Templates for Multitarget Ligand Design
[Image: see text] Compounds with multitarget activity (promiscuity) are increasingly sought in drug discovery. However, promiscuous compounds are often viewed controversially in light of potential assay artifacts that may give rise to false-positive activity annotations. We have reasoned that the st...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045467/ https://www.ncbi.nlm.nih.gov/pubmed/30023769 http://dx.doi.org/10.1021/acsomega.7b01849 |
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author | Gilberg, Erik Stumpfe, Dagmar Bajorath, Jürgen |
author_facet | Gilberg, Erik Stumpfe, Dagmar Bajorath, Jürgen |
author_sort | Gilberg, Erik |
collection | PubMed |
description | [Image: see text] Compounds with multitarget activity (promiscuity) are increasingly sought in drug discovery. However, promiscuous compounds are often viewed controversially in light of potential assay artifacts that may give rise to false-positive activity annotations. We have reasoned that the strongest evidence for true multitarget activity of small molecules would be provided by experimentally determined structures of ligand–target complexes. Therefore, we have carried out a systematic search of currently available X-ray structures for compounds forming complexes with different targets. Rather unexpectedly, 1418 such crystallographic ligands were identified, including 702 that formed complexes with targets from different protein families (multifamily ligands). About half of these multifamily ligands originated from the medicinal chemistry literature, making it possible to consider additional target annotations and search for analogues. From 168 distinct series of analogues containing one or more multifamily ligands, 133 unique analogue-series-based scaffolds were isolated that can serve as templates for the design of new compounds with multitarget activity. As a part of our study, all of the multifamily ligands we have identified and the analogue-series-based scaffolds are made freely available. |
format | Online Article Text |
id | pubmed-6045467 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-60454672018-07-16 X-ray-Structure-Based Identification of Compounds with Activity against Targets from Different Families and Generation of Templates for Multitarget Ligand Design Gilberg, Erik Stumpfe, Dagmar Bajorath, Jürgen ACS Omega [Image: see text] Compounds with multitarget activity (promiscuity) are increasingly sought in drug discovery. However, promiscuous compounds are often viewed controversially in light of potential assay artifacts that may give rise to false-positive activity annotations. We have reasoned that the strongest evidence for true multitarget activity of small molecules would be provided by experimentally determined structures of ligand–target complexes. Therefore, we have carried out a systematic search of currently available X-ray structures for compounds forming complexes with different targets. Rather unexpectedly, 1418 such crystallographic ligands were identified, including 702 that formed complexes with targets from different protein families (multifamily ligands). About half of these multifamily ligands originated from the medicinal chemistry literature, making it possible to consider additional target annotations and search for analogues. From 168 distinct series of analogues containing one or more multifamily ligands, 133 unique analogue-series-based scaffolds were isolated that can serve as templates for the design of new compounds with multitarget activity. As a part of our study, all of the multifamily ligands we have identified and the analogue-series-based scaffolds are made freely available. American Chemical Society 2018-01-05 /pmc/articles/PMC6045467/ /pubmed/30023769 http://dx.doi.org/10.1021/acsomega.7b01849 Text en Copyright © 2018 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Gilberg, Erik Stumpfe, Dagmar Bajorath, Jürgen X-ray-Structure-Based Identification of Compounds with Activity against Targets from Different Families and Generation of Templates for Multitarget Ligand Design |
title | X-ray-Structure-Based Identification of Compounds with Activity against Targets
from Different Families and Generation of Templates for Multitarget
Ligand Design |
title_full | X-ray-Structure-Based Identification of Compounds with Activity against Targets
from Different Families and Generation of Templates for Multitarget
Ligand Design |
title_fullStr | X-ray-Structure-Based Identification of Compounds with Activity against Targets
from Different Families and Generation of Templates for Multitarget
Ligand Design |
title_full_unstemmed | X-ray-Structure-Based Identification of Compounds with Activity against Targets
from Different Families and Generation of Templates for Multitarget
Ligand Design |
title_short | X-ray-Structure-Based Identification of Compounds with Activity against Targets
from Different Families and Generation of Templates for Multitarget
Ligand Design |
title_sort | x-ray-structure-based identification of compounds with activity against targets
from different families and generation of templates for multitarget
ligand design |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045467/ https://www.ncbi.nlm.nih.gov/pubmed/30023769 http://dx.doi.org/10.1021/acsomega.7b01849 |
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