Designing of dual inhibitors for GSK-3β and CDK5: Virtual screening andin vitrobiological activities study
Hongbo Xie, Haixia Wen, Denan Zhang, Lei Liu, Bo Liu, Qiuqi Liu, Qing Jin, Kehui Ke, Ming Hu, Xiujie Chen · Oncotarget · 2017
// Hongbo Xie 1, * , Haixia Wen 1, 2, * , Denan Zhang 1 , Lei Liu 1 , Bo Liu 1 , Qiuqi Liu 1 , Qing Jin 1 , Kehui Ke 1 , Ming Hu 1 , Xiujie Chen 1 1 Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, P. R. China 2 Department of Physiology, Harbin Medical University, Harbin 150086, P. R. China * These authors have contributed equally to this work Correspondence to: Hongbo Xie, email: [email protected] Xiujie Chen, email: [email protected] Keywords: Alzheimer’s disease, GSK-3 β , CDK5, multi-target Received: November 14, 2016 Accepted: January 11, 2017 Published: February 04, 2017 ABSTRACT 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 A β 25-35 - 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.