Computational discovery and experimental verification of tyrosine kinase inhibitor pazopanib for the reversal of memory and cognitive deficits in rat model neurodegeneration
Cognition and memory impairment are hallmarks of the pathological cascade of various neurodegenerative disorders. Herein, we developed a novel computational strategy with two-dimensional virtual screening for not only affinity but also specificity. We integrated the two-dimensional virtual screening with ligand screening for 3D shape, electrostatic similarity and local binding site similarity to find existing drugs that may reduce the signs of cognitive deficits. For the first time, we found that pazopanib, a tyrosine kinase inhibitor marketed for cancer treatment, inhibits acetylcholinesterase (AchE) activities at sub-micromolar concentration. We evaluated and compared the effects of intragastrically-administered pazopanib with donepezil, a marketed AchE inhibitor, in cognitive and behavioral assays including the novel object recognition test, Y maze and Morris water maze test. Surprisingly, we found that pazopanib can restore memory loss and cognitive dysfunction to a similar extent as donepezil in a dosage of 15 mg kg(-1), only one fifth of the equivalent clinical dosage for cancer treatment. Furthermore, we demonstrated that pazopanib dramatically enhances the hippocampal Ach levels and increases the expression of the synaptic marker SYP. These findings suggest that pazopanib may become a viable treatment option for memory and cognitive deficits with a good safety profile in humans.
1.Dalian Univ Technol, Sch Life Sci & Biotechnol, Ctr Mol Med, Dalian 116023, Peoples R China 2.Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Lab Mol Modeling & Design, Dalian 116023, Peoples R China 3.Shenyang Pharmaceut Univ, Dept Life Sci & Biopharmaceut, Shenyang 110016, Peoples R China 4.Chinese Acad Sci, Changchun Inst Appl Chem, State Key Lab Electroanal Chem, Changchun, Kagawa, Peoples R China 5.SUNY Stony Brook, Dept Chem & Phys, Stony Brook, NY 11794 USA
Recommended Citation:
Yang, Yongliang,Li, Guohui,Zhao, Dongyu,et al. Computational discovery and experimental verification of tyrosine kinase inhibitor pazopanib for the reversal of memory and cognitive deficits in rat model neurodegeneration[J]. CHEMICAL SCIENCE,2015,6(5):2812-2821.
