Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies.
Cyclophilin D
Fragment-based lead discovery
Fragment-screening
Inhibitor
Structure-based design
Surface plasmon resonance
X-ray structure
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 12 2019
01 12 2019
Historique:
received:
13
08
2019
revised:
19
09
2019
accepted:
21
09
2019
pubmed:
23
10
2019
medline:
12
8
2020
entrez:
23
10
2019
Statut:
ppublish
Résumé
Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1' and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization.
Identifiants
pubmed: 31635932
pii: S0960-894X(19)30675-4
doi: 10.1016/j.bmcl.2019.126717
pmc: PMC7195332
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Lactams
0
Cyclophilins
EC 5.2.1.-
PPID protein, human
EC 5.2.1.8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
126717Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
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