Structure-based drug design of novel and highly potent pyruvate dehydrogenase kinase inhibitors.
ATP binding site
Intramolecular pi-pi interaction
Novel ATP lid conformation
Pyruvate dehydrogenase kinases (PDHKs)
Structure-based drug design (SBDD)
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
15 12 2021
15 12 2021
Historique:
received:
15
09
2021
revised:
31
10
2021
accepted:
01
11
2021
pubmed:
23
11
2021
medline:
19
1
2022
entrez:
22
11
2021
Statut:
ppublish
Résumé
Pyruvate dehydrogenase kinases (PDHKs) are fascinating drug targets for numerous diseases, including diabetes and cancers. In this report, we describe the result of our structure-based drug design from tricyclic lead compounds that led to the discovery of highly potent PDHK2 and PDHK4 dual inhibitors in enzymatic assay. The C3-position of the tricyclic core was explored, and the PDHK2 X-ray structure with a representative compound revealed a novel ATP lid conformation in which the phenyl ring of Phe326 mediated the interaction of the Arg258 sidechain and the compound. Compounds with amide linkers were designed to release the ATP lid by forming an intramolecular pi-pi interaction, and these compounds showed single-digit nM IC
Identifiants
pubmed: 34808405
pii: S0968-0896(21)00522-8
doi: 10.1016/j.bmc.2021.116514
pii:
doi:
Substances chimiques
Amides
0
Protein Kinase Inhibitors
0
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
0
Adenosine Triphosphate
8L70Q75FXE
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
116514Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.