Tankyrases (TNKSs) have been implicated in many biological processes and have been proposed as a drug target for cancer therapy. The human genome encodes two homologous isoforms, TNKS-1 and TNKS-2. During the past few years, there has been an increased interest in the development of tankyrase inhibitors because of their observed therapeutic effects in selected tumor models. This study reported the first theoretical study of three-dimensional, two-dimensional quantitative structure activity relationships and a docking analysis of series of 2-arylquinazolin-4-one, 3-arylisoquinolin-1-one, arylnaphthyridinone and aryltetrahydronaphthyridinone derivatives with remarkable TNKS-2 inhibiting activities reported recently in literatures. The predictive ability of the QSAR models was assessed using internal and external validation. 3D-QSAR model showed that the substituents R1 and R2 in studied compounds are key modulators to enhance the TNKS-2 inhibition. The 2D-QSAR model, was based mainly on three 2D descriptors and nine 3D descriptors. This suggested that TNKS-2 inhibition is predominantly controlled by steric properties of the inhibitors. Docking study was carried out by using ligands docking on the active site of three different crystal structures of TNKS-2 to understand the binding mode of these compounds as TNKS-2 inhibitors. We discussed the structural requirements for selective and potent TNKS-2 inhibitors. Four potent inhibitors were designed to be synthesized in the future.
Key words: Tankyrase, QSAR, Docking, 2-arylquinazolin-4-one, 3-arylisoquinolin-1-one, arylnaphthyridinone.
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