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Virtual screening using ligand-based pharmacophores for inhibitors of human tyrosyl-DNA phospodiesterase (hTdp1)
Authors:Iwona E Weidlich  Thomas S Dexheimer  Christophe Marchand  Smitha Antony  Yves Pommier  Marc C Nicklaus
Institution:1. Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Frederick, MD 21702, USA;2. Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
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 (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.
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