10.3389/fphar.2018.00983.s001 Kiminori Hori Kiminori Hori Kasumi Ajioka Kasumi Ajioka Natsuko Goda Natsuko Goda Asako Shindo Asako Shindo Maki Takagishi Maki Takagishi Takeshi Tenno Takeshi Tenno Hidekazu Hiroaki Hidekazu Hiroaki Data_Sheet_1_Discovery of Potent Disheveled/Dvl Inhibitors Using Virtual Screening Optimized With NMR-Based Docking Performance Index.pdf Frontiers 2018 Wnt signaling protein–protein interaction inhibitor NMR-derived docking performance index virtual screening triple negative breast cancer 2018-09-05 13:55:16 Dataset https://frontiersin.figshare.com/articles/dataset/Data_Sheet_1_Discovery_of_Potent_Disheveled_Dvl_Inhibitors_Using_Virtual_Screening_Optimized_With_NMR-Based_Docking_Performance_Index_pdf/7048769 <p>Most solid tumors have their own cancer stem cells (CSCs), which are resistant to standard chemo-therapies. Recent reports have described that Wnt pathway plays a key role in self-renewal and tumorigenesis of CSCs. Regarding the Wnt/β-catenin pathway, Dvl (mammalian Disheveled) is an attractive target of drug discovery. After analyzing the PDZ domain of human Dvl1 (Dvl1-PDZ) using NMR, we subjected it to preliminary NMR titration studies with 17 potential PDZ-binding molecules including CalBioChem-322338, a commercially available Dvl PDZ domain inhibitor. Next, we performed virtual screening (VS) using the program GOLD with nine parameter sets. Results were evaluated using the NMR-derived docking performance index (NMR-DPI). One parameter set of GOLD docking showing the best NMR-DPI was selected and used for the second VS against 5,135 compounds. The second docking trial identified more than 1,700 compounds that exhibited higher scores than CalBioChem-322338. Subsequent NMR titration experiments with five new candidate molecules (NPL-4001, 4004, 4011, 4012, and 4013), Dvl1-PDZ revealed larger chemical shift changes than those of CalBioChem-322338. Finally, these compounds showed partial proliferation inhibition activity against BT-20, a triple negative breast cancer (TNBC) cell. These compounds are promising Wnt pathway inhibitors that are potentially useful for anti-TNBC therapy.</p>