Machine Learning-Based Virtual Screening for the Identification of Cdk5 Inhibitors
Miriana Di StefanoSalvatore GalatiGabriella OrtoreIsabella CaligiuriFlavio RizzolioCostanza CeniSimone BertiniGiulia BononiCarlotta GranchiMarco MacchiaGiulio PoliTiziano Tuccinardi
17
Citation
51
Reference
10
Related Paper
Citation Trend
Abstract:
Cyclin-dependent kinase 5 (Cdk5) is an atypical proline-directed serine/threonine protein kinase well-characterized for its role in the central nervous system rather than in the cell cycle. Indeed, its dysregulation has been strongly implicated in the progression of synaptic dysfunction and neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and also in the development and progression of a variety of cancers. For this reason, Cdk5 is considered as a promising target for drug design, and the discovery of novel small-molecule Cdk5 inhibitors is of great interest in the medicinal chemistry field. In this context, we employed a machine learning-based virtual screening protocol with subsequent molecular docking, molecular dynamics simulations and binding free energy evaluations. Our virtual screening studies resulted in the identification of two novel Cdk5 inhibitors, highlighting an experimental hit rate of 50% and thus validating the reliability of the in silico workflow. Both identified ligands, compounds CPD1 and CPD4, showed a promising enzyme inhibitory activity and CPD1 also demonstrated a remarkable antiproliferative activity in ovarian and colon cancer cells. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent Cdk5 inhibitors.Keywords:
Identification
Cyclin-dependent kinase 5
Cyclin-dependent kinase 5
Neuronal migration
Cite
Citations (0)
Cyclin-dependent kinase 5
Cite
Citations (169)
Cyclin-dependent kinase 5
Cite
Citations (0)
The application of Virtual screening method as an important tool in our quest to access novel drug like compounds. There are a large range of comparable and contrasting methodological protocols available in screening databases for the lead compounds. The number of methods and software packages which employ the target and ligand based virtual screening are increasing at a rapid rate. However, the general understanding on the applicability and limitations of these methodologies is not emerging as fast as the developments of various methods. Virtual screening uses computer based methods to discover new ligands on the basis of biological structures. Virtual screening is divided into structural based screening (docking) and screening using active compounds as templates (ligand based virtual screening). Ligand based screening techniques mainly focus on comparing molecular similarity analyses of compounds with known and unknown moiety, regardless of the methods of the used algorithm. Docking is a computational tool of structure based drug design to predict protein ligand interaction geometries and binding affinities. In this review we provide an overview of the already used ligand based virtual screening and the docking with various databases, filters, scores and applications in the recent research in the pharmaceutical field.
Protein–ligand docking
Docking (animal)
Binding affinities
Cite
Citations (0)
Cyclin-dependent kinase 5
Drug Development
Tau protein
Pathogenesis
Cite
Citations (65)
Cyclin‐dependent kinase‐5 (Cdk5) is a serine/threonine kinase activated by its neuron‐specific activator, p35, or its truncated form, p25. It has been proposed that the deregulation of Cdk5 activity by association with p25 in human brain tissue disrupts the neuronal cytoskeleton and may be involved in neurodegenerative diseases such as Alzheimer's disease. In this study, we demonstrate that a short peptide (amino acid residues 154–279; Cdk5 inhibitory peptide; CIP), derived from p35, specifically inhibits Cdk5 activity invitro and in HEK293 cells cotransfected with the peptideand Cdk5/p25, but had no effect on endogenous cdc2 kinaseactivity. Moreover, we demonstrate that the phosphorylation of tau in HEK293 cells, cotransfected with Cdk5/p25 and CIP, is effectively reduced. These results suggest that CIP specifically inhibits both Cdk5/p25 complex activity and the tau hyperphosphorylation induced by Cdk5/p25. The elucidation of the molecular basis of p25 activation and CIP inhibition of Cdk5 activity may provide insight into mechanisms underlying the pathology of Alzheimer's disease and contribute to therapeutic strategies.
Cyclin-dependent kinase 5
Hyperphosphorylation
HEK 293 cells
Cite
Citations (79)
Cyclin-dependent kinase 5
Cite
Citations (13)
We study the role of CDK5 in mammalian development. Although a member of the cyclin dependent kinase family, CDK5 has been shown to influence differentiation of non‐dividing nervous tissues. Previously, our lab has used PC12 cells to study CDK5's role in neuronal development. Experiments involving growth factor‐induced (NGF, FGF) differentiation of PC12 cells in the presence of CDK5 inhibitors resulted in drastic morphological changes. Recent reports suggest CDK5 may also play an extra neuronal role. Here we report the impact of CDK5 manipulation in pancreatic tissue using the acinar cell line AR42J. The transdiffereniation of these cells from non‐insulin producing (acinar) to insulin producing (beta‐like) cells was induced by the administration of the chemical exendin‐4. Cells were assayed for the insulin phenotype, with a primary rat islet cell line used as a positive control. To asses the role of CDK5 in the pathway to this phenotype, insulin levels were quantified following simultaneous treatment of these cells with both exendin‐4 and the CDK5 specific inhibitor, olomoucine. Results suggest a role for CDK5 in the acquisition of this insulin phenotype. This data, coupled with the neurological role of CDK5, suggests a correlation between pathologies such as Alzheimer's disease and Type 2 Diabetes.
Cyclin-dependent kinase 5
Cite
Citations (1)
Cyclin-dependent kinase 5
ASK1
Cyclin-dependent kinase 4
Cite
Citations (0)
Cyclin-dependent kinase 5
Remyelination
Cite
Citations (14)