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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...

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Autores principales: Gilberg, Erik, Stumpfe, Dagmar, Bajorath, Jürgen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2018
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.
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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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