Designing of dual inhibitors for GSK-3β and CDK5: Virtual screening and in vitro biological activities study.
Alzheimer's disease is a multifactorial neurodegenerative disorder with many drug targets contributing to its etiology. Despite the devastating effects of this disease, therapeutic methods for treating Alzheimer's disease remain limited. The multifactorial nature of Alzheimer's disease strongly supports a multi-target rationale as a drug design strategy. Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 have been identified as being involved in the pathological hyperphosphorylation of tau proteins, which leads to the formation of neurofibrillary tangles and causes Alzheimer's disease. In this study, using a molecular docking method to screen a virtual library, we discovered molecules that can simultaneously inhibit Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 as lead compounds for the treatment of Alzheimer's disease. The docking results revealed the key residues in the substrate binding sites of both Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5. A receiver operating characteristic curve indicated that the docking model consistently and selectively scored the majority of active compounds above decoys. The pre-treatment of cells with screened compounds protected them against Aβ25-35- induced cell death by up to 80%. Collectively, these findings suggest that some compounds have potential to be promising multifunctional agents for Alzheimer's disease treatment.
Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, P. R. China.
Hongbo
H
Xie
Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, P. R. China.|Department of Physiology, Harbin Medical University, Harbin 150086, P. R. China.
Haixia
H
Wen
Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, P. R. China.
Denan
D
Zhang
Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, P. R. China.
Lei
L
Liu
Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, P. R. China.
Bo
B
Liu
Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, P. R. China.
Qiuqi
Q
Liu
Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, P. R. China.
Qing
Q
Jin
Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, P. R. China.
Kehui
K
Ke
Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, P. R. China.
Ming
M
Hu
Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, P. R. China.
Xiujie
X
Chen
D000544:Alzheimer Disease; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors*; D006801:Humans; D062105:Molecular Docking Simulation; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D012372:ROC Curve
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C495905:CDK5 protein, human
Alzheimer’s disease; CDK5; GSK-3β; multi-target