Development of Novel Selective Pharmacophore for Tankyrase Inhibitors

Background: Tankyrases, members of PARP protein superfamily, are involved in many cellular processes and play key roles in Wnt signaling and in several diseases including cancers. During the past few years, there has been an increased interest in the development of selective smallmolecular tankyrase inhibitors. Objective: The objective was to construct a novel selective pharmacophore model for tankyrase inhibitors. Methods: In this paper, the novel selective pharmacophore model was constructed using a combination of computational methods, including molecular docking, protein-ligand interaction fingerprint (PLIF) similarity investigation, 3D-QSAR pharmacophore merging, binding site analysis like protein sequence alignment, SiteMap and FTMap. Results: Within these analyses, a novel selective pharmacophore model was constructed. The two HY features were located in the induced pocket and the sub-pocket, respectively. The hydrogen bond acceptor (HBA) feature corresponding to Tyr1213 was located in the sub-pocket. To assess the reliability and validity of the pharmacophore, the model was then applied to screen two validation databases for highly selective tankyrase inhibitors. The high values of enrichment factor (32.61; 34.52) and receiver operating characteristic (ROC) score (0.853; 0.805) indicated the model performed fairly well at distinguishing the selective tankyrase inhibitors from putative inactive compounds. Furthermore, 12 highly selective inhibitors (10000-fold) were all ranked in the forefront of screening results. Conclusion: The pharmacophore model reflects the most important binding requirements for the selective tankyrase inhibitors, and the results can provide new insights for design and discovery of novel tankyrase inhibitors with high selectivity.