title: Inhibitors of human tyrosyl-DNA phospodiesterase (hTdp1) developed by virtual screening using ligand-based pharmacophores.
abstract: Human tyrosyl-DNA phosphodiesterase (hTdp1) inhibitors have become a major area of drug research and structure-based design since they have been shown to work synergistically with camptothecin (CPT) and selectively in cancer cells. The pharmacophore features of 14 hTdp1 inhibitors were used as a filter to screen the ChemNavigator iResearch Library of about 27 million purchasable samples. Docking of the inhibitors and hits obtained from virtual screening was performed into a structural model of hTdp1 based on a high resolution X-ray crystal structure of human Tdp1 in complex with vanadate, DNA and a human topoisomerase I (TopI)-derived peptide (PDB code: 1NOP). A total of 46 compounds matching the three-dimensional arrangement of the pharmacophoric features were assayed. Using a high-throughput screening assay, we have identified an 1H-indol-3-yl-acetic acid derivative as a potent Tdp1 inhibitor with an IC(50) value of 7.94 microM. The obtained novel chemotype may provide a new scaffold for developing inhibitors of Tdp1.
authors: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Frederick, MD 21702, USA.
authors: Iwona E
authors: IE
authors: Weidlich
authors: Thomas
authors: T
authors: Dexheimer
authors: Christophe
authors: C
authors: Marchand
authors: Smitha
authors: S
authors: Antony
authors: Yves
authors: Y
authors: Pommier
authors: Marc C
authors: MC
authors: Nicklaus
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; C122147:tyrosyl-DNA phosphodiesterase