Inhibitors of human tyrosyl-DNA phospodiesterase (hTdp1) developed by virtual screening using ligand-based pharmacophores

详细信息    查看全文

• 作者：Iwona E. Weidlich ; Thomas Dexheimer ; Christophe March ; Smitha Antony ; Yves Pommier ; Marc C. Nicklaus
• 关键词：Human tyrosyl-DNA phosphodiesterase ; Tdp1 ; Inhibitors ; Small molecule docking ; Drug design ; Virtual screening
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2010
• 出版时间：1 January 2010
• 年：2010
• 卷：18
• 期：1
• 页码：182-189
• 全文大小：687 K

文摘

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<sub>50sub> value of 7.94 μM. The obtained novel chemotype may provide a new scaffold for developing inhibitors of Tdp1.