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). 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.

Dual DNA topoisomerase 1 and tyrosyl‐DNA phosphodiesterase 1 inhibition for improved anticancer activity

“…In addition, Tdp1 is gathering interest in cancer treatment because of its role in repairing various other DNA adducts induced by chemotherapeutics . Recently, new classes of Tdp1 inhibitors have been developed that are active in the micromolar to nanomolar range and have low intrinsic toxicity …”

“…38,39,44 Recently, new classes of Tdp1 inhibitors have been developed that are active in the micromolar to nanomolar range and have low intrinsic toxicity. 39,43,52,60,[64][65][66][67][71][72][73]84 Using the same compounds to inhibit Tdp1 and Top1 is a prospective approach to develop anticancer drugs as both Tdp1 and Tdp2 inhibition could hypothetically potentiate the cytotoxicities of topoisomerase poisons. This review is devoted to study the combined inhibition of Top1 and Tdp1, as well as Tdp2 for triple inhibitors.…”

“…Many other compounds have been identified as Tdp1 inhibitors from various chemical classes including orthovanadates and tungstates, progesterone derivatives, piperidinyl sulfamides, benzopentathiepine, sulfonic acid, diamidine, bile acids, thieno[2,3‐b]pyridine derivatives, aminoglycoside antibiotics, ribosome inhibitors, halenaquinones, and 5 arylidenethioxothiazolidinones . These compounds were generated for the inhibition of Tdp1 only, and some of them were analyzed as sensitizers of tumor cells to the action of Top1 poisons.…”

“…52 Lead compound 41a potentiated the effect of camptothecin in MCF-7 cells. 66 halenaquinones, 66 and 5-arylidenethioxothiazolidinones. 67 These compounds were generated for the inhibition of Tdp1 only, and some of them were analyzed as sensitizers of tumor cells to the action of Top1 poisons.…”

Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies

“…Sequential, parallel or hybrid combinations of VS techniques take into account all available chemical and biological information and thereby mitigate the drawbacks of each individual method (Figure 6 ; Hein et al, 2010 ; Wilson and Lill, 2011 ). Most of the recently published CADD studies apply a sequential VS approach (Khan et al, 2010 ; Weidlich et al, 2010 ; Drwal et al, 2011 ; Banoglu et al, 2012 ). In this approach ligand- and structure-based strategies are used in the VS protocol to gradually filter the large databases until the number of remaining potential hit compounds is small enough for biological testing.…”