π-Stacking Interactions Involved in Gynecologic Tankyrase-1/Inhibitor Recognition and Association: Implications for Rational Design of Aromatic Pentapeptide Ligands

Human tankyrase-1 is an important regulator of poly(ADP-ribosyl)ation (PARylation) of Wnt/β-catenin signaling and has been recognized as a druggable target of gynecologic tumors. The active site of tankyrase-1 is rich with π-electron, which contains a number of aromatic amino aid residues and can form multiple π-stacking interactions with its substrates and ligands. In this study, computational analysis revealed that aromatic residues involved in tankyrase-1’s active site are significantly responsible for the intermolecular interaction between tankyrase-1 and its inhibitor ligands. Based on the harvested information, structure-based molecular design of aromatic pentapeptide inhibitors was carried out to target tankyrase-1. The pentapeptide candidates were defined by aromatic amino acids, and their π-stacking contribution is stronger than small-molecule inhibitors. Eight pentapeptide hits were determined to have moderate or high inhibitory potency against human tankyrase-1, in which two hits FYWYH and YWFYH can inhibit the enzyme potently at sub-micromolar level. Structural analysis observed a number of face-to-face, parallel-displaced and T-shaped π-stacking interactions at tankyrase-1/pentapeptide complex interface, which co-define a complicated π-stacking network and confer both stability and specificity for the complex formation.