Title | Identifying New Ligands for JNK3 by Fluorescence Thermal Shift Assays and Native Mass Spectrometry |
Authors | Cheng, Chongyun Liu, Miaomiao Gao, Xiaoqin Wu, Dong Pu, Mengchen Ma, Jun Quinn, Ronald J. Xiao, Zhicheng Liu, Zhijie |
Affiliation | Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China Griffith Univ, Griffith Inst Drug Discovery, Brisbane, Qld 4111, Australia Monash Univ, Monash Biomed Discovery Inst, Melbourne, Vic 3800, Australia Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China ShanghaiTech Univ, IHuman Inst, Shanghai 201210, Peoples R China Kunming Med Coll, Kunming 650031, Yunnan, Peoples R China |
Keywords | N-TERMINAL KINASES INHIBITORS OPTIMIZATION ACTIVATION INDUCTION DOCKING NEURONS SURFACE DESIGN POTENT |
Issue Date | 26-Apr-2022 |
Publisher | ACS OMEGA |
Abstract | The c-Jun N-terminal kinases (JNKs) are evolutionary highly conserved serine/threonine kinases. Numerous findings suggest that JNK3 is involved in the pathogenesis of neurodegenerative diseases, so the inhibition of JNK3 may be a potential therapeutic intervention. The identification of novel compounds with promising pharmacological properties still represents a challenge. Fluorescence thermal shift screening of a chemically diversified lead-like scaffold library of 2024 pure compounds led to the initial identification of seven JNK3 binding hits, which were classified into four scaffold groups according to their chemical structures. Native mass spectrometry validated the interaction of 4 out of the 7 hits with JNK3. Binding geometries and interactions of the top 2 hits were evaluated by docking into a JNK3 crystal structure. Hit 5 had a Kd of 21 mu M with JNK3 suggested scaffold 5-(phenylamino)-1H-1,2,3-triazole-4-carboxamide as a novel and selective JNK3 binder. |
URI | http://hdl.handle.net/20.500.11897/648143 |
ISSN | 2470-1343 |
DOI | 10.1021/acsomega.2c00340 |
Indexed | SCI(E) |
Appears in Collections: | 药学院 天然药物与仿生药物国家重点实验室 |