2. Academic Validation
  3. Discovery of a novel DYRK1A inhibitor with neuroprotective activity by virtual screening and in vitro biological evaluation

Discovery of a novel DYRK1A inhibitor with neuroprotective activity by virtual screening and in vitro biological evaluation

  • Mol Divers. 2024 Jun 4. doi: 10.1007/s11030-024-10856-2.
Xinxin Si # 1,  Chenliang Qian # 1 2,  Nianzhuang Qiu # 3,  Yaling Wang 1 2,  Mingli Yao 1 2,  Hao Wang 4,  Xuehui Zhang 5,  Jie Xia 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, Jiangsu, China.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 2 Nanwei Road, Beijing, 100050, China.
  • 3 School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China.
  • 4 School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China. tywanghao_2005@163.com.
  • 5 School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China. zhangxuehui@sdfmu.edu.cn.
  • 6 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 2 Nanwei Road, Beijing, 100050, China. jie.william.xia@hotmail.com.
  • # Contributed equally.
PMID: 38833123 DOI: 10.1007/s11030-024-10856-2
Abstract

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is implicated in accumulation of amyloid β-protein (Aβ) and phosphorylation of Tau proteins, and thus represents an important therapeutic target for neurodegenerative diseases. Though many DYRK1A inhibitors have been discovered, there is still no marketed drug targeting DYRK1A. This is partly due to the lack of effective and safe chemotypes. Therefore, it is still necessary to identify new classes of DYRK1A inhibitors. By performing virtual screening with the workflow mainly composed of pharmacophore modeling and molecular docking as well as the following DYRK1A inhibition assay, we identified compound L9, ((Z)-1-(((5-phenyl-1H-pyrazol-4-yl)methylene)-amino)-1H-tetrazol-5-amine), as a moderately active DYRK1A inhibitor (IC50: 1.67 μM). This compound was structurally different from the known DYRK1A inhibitors, showed a unique binding mode to DYRK1A. Furthermore, compound L9 showed neuroprotective activity against okadaic acid (OA)-induced injury in the human neuroblastoma cell line SH-SY5Y by regulating the expression of Aβ and phosphorylation of Tau Protein. This compound was neither toxic to the SH-SY5Y cells nor to the human normal liver cell line HL-7702 (IC50: >100 μM). In conclusion, we have identified a novel DYRK1A inhibitor with neuroprotective activity through virtual screening and in vitro biological evaluation, which holds the promise for further study.

Keywords

DYRK1A; Molecular docking; Molecular dynamics simulation; Pharmacophore model; Virtual screening.

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