Stereochemically-aware bioactivity descriptors for uncharacterized chemical compounds.
Small molecule bioactivity descriptors
Stereochemistry
Target-compound binding
Journal
Journal of cheminformatics
ISSN: 1758-2946
Titre abrégé: J Cheminform
Pays: England
ID NLM: 101516718
Informations de publication
Date de publication:
18 Jun 2024
18 Jun 2024
Historique:
received:
25
03
2024
accepted:
05
06
2024
medline:
19
6
2024
pubmed:
19
6
2024
entrez:
18
6
2024
Statut:
epublish
Résumé
Stereochemistry plays a fundamental role in pharmacology. Here, we systematically investigate the relationship between stereoisomerism and bioactivity on over 1 M compounds, finding that a very significant fraction (~ 40%) of spatial isomer pairs show, to some extent, distinct bioactivities. We then use the 3D representation of these molecules to train a collection of deep neural networks (Signaturizers3D) to generate bioactivity descriptors associated to small molecules, that capture their effects at increasing levels of biological complexity (i.e. from protein targets to clinical outcomes). Further, we assess the ability of the descriptors to distinguish between stereoisomers and to recapitulate their different target binding profiles. Overall, we show how these new stereochemically-aware descriptors provide an even more faithful description of complex small molecule bioactivity properties, capturing key differences in the activity of stereoisomers.Scientific contributionWe systematically assess the relationship between stereoisomerism and bioactivity on a large scale, focusing on compound-target binding events, and use our findings to train novel deep learning models to generate stereochemically-aware bioactivity signatures for any compound of interest.
Identifiants
pubmed: 38890727
doi: 10.1186/s13321-024-00867-4
pii: 10.1186/s13321-024-00867-4
doi:
Types de publication
Journal Article
Langues
eng
Pagination
70Subventions
Organisme : Generalitat de Catalunya
ID : 2021 SGR 00876
Organisme : Ministerio de Ciencia, Innovación y Universidades
ID : PID2020-119535RB-I00
Organisme : Instituto de Salud Carlos III
ID : IMPaCT-Data
Organisme : European Commission
ID : CLARITY: 101137201
Informations de copyright
© 2024. The Author(s).
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