Computer-aided drug design of small molecule inhibitors of the ERCC1-XPF protein-protein interaction.
Cross-Linking Reagents
/ chemistry
DNA Damage
/ drug effects
DNA Repair
/ drug effects
DNA-Binding Proteins
/ metabolism
Drug Design
Endonucleases
/ antagonists & inhibitors
Enzyme Inhibitors
/ chemistry
Humans
Molecular Dynamics Simulation
Platinum
/ chemistry
Protein Binding
Small Molecule Libraries
/ chemistry
Structure-Activity Relationship
DNA repair
ERCC1-XPF
chemotherapy
computer-aided drug design
molecular dynamics
protein
protein interaction
small molecules
virtual screening
Journal
Chemical biology & drug design
ISSN: 1747-0285
Titre abrégé: Chem Biol Drug Des
Pays: England
ID NLM: 101262549
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
20
09
2019
revised:
15
11
2019
accepted:
17
12
2019
pubmed:
1
1
2020
medline:
19
5
2021
entrez:
1
1
2020
Statut:
ppublish
Résumé
The heterodimer of DNA excision repair protein ERCC-1 and DNA repair endonuclease XPF (ERCC1-XPF) is a 5'-3' structure-specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1-XPF plays a central role in repairing DNA damage induced by chemotherapeutics including platinum-based and cross-linking agents; thus, its inhibition is a promising strategy to enhance the effect of these therapies. In this study, we rationally modified the structure of F06, a small molecule inhibitor of the ERCC1-XPF interaction (Molecular Pharmacology, 84, 2013 and 12), to improve its binding to the target. We followed a multi-step computational approach to investigate potential modification sites of F06, rationally design and rank a library of analogues, and identify candidates for chemical synthesis and in vitro testing. Our top compound, B5, showed an improved half-maximum inhibitory concentration (IC
Substances chimiques
Cross-Linking Reagents
0
DNA-Binding Proteins
0
Enzyme Inhibitors
0
Small Molecule Libraries
0
xeroderma pigmentosum group F protein
0
Platinum
49DFR088MY
ERCC1 protein, human
EC 3.1.-
Endonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
460-471Informations de copyright
© 2019 John Wiley & Sons A/S.
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