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Computational Simulations Identify Pyrrolidine-2,3-Dione Derivatives as Novel Inhibitors of Cdk5/p25 Complex to Attenuate Alzheimer’s Pathology

Published on May 24, 2019in Journal of Clinical Medicine5.688
· DOI :10.3390/jcm8050746
Amir Zeb5
Estimated H-index: 5
,
Donghwan Kim1
Estimated H-index: 1
+ 9 AuthorsKeun Woo Lee30
Estimated H-index: 30
Abstract
Mechanistically, neurotoxic insults provoke Ca2+-mediated calpain activation, which cleaves the cytoplasmic region of membrane-embedded p35 and produces its truncated form p25. Upon physical interaction, cyclin-dependent kinase 5 (Cdk5) and p25 forms hyperactivated Cdk5/p25 complex and causes severe neuropathological aberrations including hyperphosphorylated tau-mediated neurofibrillary tangles formation, Alzheimer’s symptoms, and neuronal death. Therefore, the inhibition of Cdk5/p25 complex may relieve p-tau-mediated Alzheimer’s pathology. Herein, computational simulations have identified pyrrolidine-2,3-dione derivatives as novel inhibitors of Cdk5/p25 complex. A ligand-based pharmacophore was designed and employed as 3D query to retrieve drug-like molecules from chemical databases. By molecular docking, drug-like molecules obtaining dock score > 67.67 (Goldcore of the reference compound) were identified. Molecular dynamics simulation and binding free energy calculation retrieved four pyrrolidine-2,3-dione derivatives as novel candidate inhibitors of Cdk5/p25. The root means square deviation of Cdk5/p25 in complex with candidate inhibitors obtained an average value of ~2.15 A during the 30 ns simulation period. Molecular interactions analysis suggested that each inhibitor occupied the ATP-binding site of Cdk5/p25 and formed stable interactions. Finally, the binding free energy estimation suggested that each inhibitor had lowest binding energy than the reference compound (−113.10 kJ/mol) to recapitulate their strong binding with Cdk5/p25. Overall, these inhibitors could mitigate tau-mediated Alzheimer’s phenotype.
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