Comprehensive detection and characterization of human druggable pockets through binding site descriptors.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 Sep 2024
10 Sep 2024
Historique:
received:
04
03
2024
accepted:
27
08
2024
medline:
11
9
2024
pubmed:
11
9
2024
entrez:
10
9
2024
Statut:
epublish
Résumé
Druggable pockets are protein regions that have the ability to bind organic small molecules, and their characterization is essential in target-based drug discovery. However, deriving pocket descriptors is challenging and existing strategies are often limited in applicability. We introduce PocketVec, an approach to generate pocket descriptors via inverse virtual screening of lead-like molecules. PocketVec performs comparably to leading methodologies while addressing key limitations. Additionally, we systematically search for druggable pockets in the human proteome, using experimentally determined structures and AlphaFold2 models, identifying over 32,000 binding sites across 20,000 protein domains. We then generate PocketVec descriptors for each site and conduct an extensive similarity search, exploring over 1.2 billion pairwise comparisons. Our results reveal druggable pocket similarities not detected by structure- or sequence-based methods, uncovering clusters of similar pockets in proteins lacking crystallized inhibitors and opening the door to strategies for prioritizing chemical probe development to explore the druggable space.
Identifiants
pubmed: 39256431
doi: 10.1038/s41467-024-52146-3
pii: 10.1038/s41467-024-52146-3
doi:
Substances chimiques
Proteins
0
Proteome
0
Ligands
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7917Subventions
Organisme : European Commission (EC)
ID : 101003633
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : IMPaCT-Data
Informations de copyright
© 2024. The Author(s).
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