title: Discovery of new dual binding TNKS inhibitors of Wnt signaling inhibition by pharmacophore modeling, molecular docking and bioassay.
abstract: Tankyrases (TNKS), key transmitters in the Wnt signaling pathway which is very conservative in evolution, are vital targets as they are overexpressed widely in many cancers. In this work, 5 inhibitors with novel structures have been discovered and validated using the ligand-based (pharmacophore) virtual screening, docking study, and Luciferase reporter assays for Wnt signaling. Among them, PYL-1, in particular, was the most potent inhibitor with an IC50value of 9.56 μM against Wnt signaling. The analysis of binding modes was performed to further understand the vital interactions between inhibitors and TNKS 2, and the five hits belong to dual site inhibitors. This work could be helpful for the design and development of novel dual binders as TNKS inhibitors.
authors.affiliation: School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong, China and State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. zuozhili@mail.kib.ac.cn.
authors.forename: Yinglan
authors.initials: Y
authors.lastname: Pu
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. zuozhili@mail.kib.ac.cn.
authors.forename: Shuqun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. zuozhili@mail.kib.ac.cn.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. zuozhili@mail.kib.ac.cn.
authors.forename: Yunqin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. zuozhili@mail.kib.ac.cn.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. zuozhili@mail.kib.ac.cn and Yunnan Key Laboratory of Natural Medicinal Chemistry, Yunnan, 650201, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. zuozhili@mail.kib.ac.cn and Yunnan Key Laboratory of Natural Medicinal Chemistry, Yunnan, 650201, China.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D016000:Cluster Analysis; D003198:Computer Simulation; D055808:Drug Discovery; D020128:Inhibitory Concentration 50; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D038501:Tankyrases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D057188:Workflow
chemical_list: D008024:Ligands; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D038501:Tankyrases