Virtual screening using ligand-based pharmacophores for inhibitors of human tyrosyl-DNA phospodiesterase (hTdp1).

Autor: Weidlich IE; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Frederick, MD 21702, USA., Dexheimer TS; Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA., Marchand C; Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA., Antony S; Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA., Pommier Y; Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA., Nicklaus MC; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Frederick, MD 21702, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2010 Mar 15; Vol. 18 (6), pp. 2347-2355. Date of Electronic Publication: 2010 Mar 02.
DOI: 10.1016/j.bmc.2010.02.009
Abstrakt: 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 14hTdp1 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 (Top1)-derived peptide (PDB code: 1NOP). We present and discuss in some detail 46 compounds matching the three-dimensional arrangement of the pharmacophoric features. The presented novel chemotypes may provide new scaffolds for developing inhibitors of Tdp1.
(Copyright © 2010. Published by Elsevier Ltd.)
Databáze: MEDLINE
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