Free energy perturbation in the design of EED ligands as inhibitors of polycomb repressive complex 2 (PRC2) methyltransferase.
EED
EZH2
Free Energy Perturbation
Late stage functionalisation
PRC2
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
01 05 2021
01 05 2021
Historique:
received:
17
11
2020
revised:
10
02
2021
accepted:
21
02
2021
pubmed:
9
3
2021
medline:
2
9
2021
entrez:
8
3
2021
Statut:
ppublish
Résumé
Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line.
Identifiants
pubmed: 33684441
pii: S0960-894X(21)00130-X
doi: 10.1016/j.bmcl.2021.127904
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Ligands
0
Purines
0
triazolopyrimidinone
273-40-5
Polycomb Repressive Complex 2
EC 2.1.1.43
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
127904Informations de copyright
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