PUBLICATION
Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft
- Authors
- Kossmann, B.R., Abdelmalak, M., Lopez, S., Tender, G., Yan, C., Pommier, Y., Marchand, C., Ivanov, I.
- ID
- ZDB-PUB-170720-20
- Date
- 2016
- Source
- Bioorganic & medicinal chemistry letters 26: 3232-6 (Journal)
- Registered Authors
- Keywords
- Inhibitor, Rational drug design, TDP2, Tyrosyl-DNA phosphodiesterase 2, Virtual screening
- MeSH Terms
-
- Animals
- Dose-Response Relationship, Drug
- Drug Discovery*
- Humans
- Mice
- Molecular Dynamics Simulation
- Molecular Structure
- Nuclear Proteins/antagonists & inhibitors*
- Nuclear Proteins/metabolism
- Phosphodiesterase Inhibitors/chemical synthesis
- Phosphodiesterase Inhibitors/chemistry
- Phosphodiesterase Inhibitors/pharmacology*
- Phosphoric Diester Hydrolases/metabolism
- Structure-Activity Relationship
- Transcription Factors/antagonists & inhibitors*
- Transcription Factors/metabolism
- Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/antagonists & inhibitors*
- Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/metabolism
- Zebrafish
- PubMed
- 27262595 Full text @ Bioorg. Med. Chem. Lett.
Citation
Kossmann, B.R., Abdelmalak, M., Lopez, S., Tender, G., Yan, C., Pommier, Y., Marchand, C., Ivanov, I. (2016) Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft. Bioorganic & medicinal chemistry letters. 26:3232-6.
Abstract
Tyrosyl-DNA phosphodiesterase 2 (TDP2) processes protein/DNA adducts resulting from abortive DNA topoisomerase II (Top2) activity. TDP2 inhibition could provide synergism with the Top2 poison class of chemotherapeutics. By virtual screening of the NCI diversity small molecule database, we identified selective TDP2 inhibitors and experimentally verified their selective inhibitory activity. Three inhibitors exhibited low-micromolar IC50 values. Molecular dynamics simulations revealed a common binding mode for these inhibitors, involving association to the TDP2 DNA-binding cleft. MM-PBSA per-residue energy decomposition identified important interactions of the compounds with specific TDP2 residues. These interactions could provide new avenues for synthetic optimization of these scaffolds.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping