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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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Weidlich IE,Dexheimer T,Marchand C,Antony S,Pommier Y,Nicklaus MC

doi

10.1016/j.bmc.2009.11.008

subject

Has Abstract

pub_date

2010-01-01 00:00:00

pages

182-9

issue

1

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(09)01016-5

journal_volume

18

pub_type

杂志文章

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