Sighting of tankyrase inhibitors by structure- and ligand-based screening and in vitro approach.

Tankyrase 1 and 2 (TNKS) are promising and attractive therapeutic targets in anticancer drug development. Herein, we report the findings of structure- and ligand-based virtual screening for novel TNKS1 inhibitors using iterative rounds of in silico studies and subsequent biological evaluation methods. Upon screening of three compound databases, a final set of five molecules were selected for experimental validation. In order to prove our in silico findings, tankyrase activity was assessed by a calorimetric assay with the five identified lead molecules. Out of five, only C1 (7309981) showed significant inhibition of TNKS1 enzyme. Furthermore, the toxicity of the selected 5 compounds was measured using cytotoxicity experiments and inhibition of cell growth, and it was more pronounced in C1, followed by C5 and C3 (7309981 > 7245236 > 7275738). The morphological assessment, DNA damage and chromatin condensation and fragmentation results also confirmed that C1 has enhanced activity against MCF-7 cells.