title: Sighting of tankyrase inhibitors by structure- and ligand-based screening and in vitro approach.
abstract: 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.
authors.affiliation: Department of Bioinformatics, Science Block, Alagappa University, Karaikudi - 630 004, Tamil Nadu, India. mkbioinformatics@gmail.com.
authors.forename: Palani
authors.initials: P
authors.lastname: Kirubakaran
authors.forename: Pitchaimani
authors.initials: P
authors.lastname: Arunkumar
authors.forename: Kumpati
authors.initials: K
authors.lastname: Premkumar
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Muthusamy
mesh_terms: D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D055808:Drug Discovery; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D038501:Tankyrases / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D038501:Tankyrases; C437334:TNKS2 protein, human; C418109:TNKS protein, human