کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1360322 | 981433 | 2010 | 8 صفحه PDF | دانلود رایگان |

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 IC50 value of 7.94 μM. The obtained novel chemotype may provide a new scaffold for developing inhibitors of Tdp1.
Compound 15 found as an inhibitor of Tdp1.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry - Volume 18, Issue 1, 1 January 2010, Pages 182–189