Related Experiment Video
Updated: Dec 1, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Identification of small molecules against cyclin dependent kinase-5 using chemoinformatics approach for Alzheimer's
Rohit Shukla1, Tiratha Raj Singh1
1Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology (JUIT), Waknaghat, India.
Abstract:
Alzheimer's disease (AD) is a multifactorial complex and wide spreading global disease. It is a chronic neurodegenerative disorder characterized by amyloid beta (Aβ) and neurofibrillary tangles (NFTs). Several enzymes are involved in which CDK5 is a major tau phosphorylation enzyme. We have screened (n = 5,36,801) compounds against CDK5 and 392 compounds were selected for pharmacokinetics analysis. In the pharmacokinetics analysis, various descriptors were used for filtering the compounds. After that 16 compounds with the control compound Z3R were employed for the redocking using Autodock Vina and Autodock. Lastly, four compounds were selected and employed for 100 ns MDS studies. On the basis of various MD analysis like RMSD, RMSF, Rg, SASA, Number of hydrogen bonds, Principal component analysis and binding free energy (CDK5-ZINC6261568: -129.50 kJ.mol-1 and CDK5-ZINC14168360: -191.16 kJ.mol-1), we have found that ZINC6261568 and ZINC14168360 can act as a lead compound against the CDK5.Communicated by Ramaswamy H. Sarma.
Insights
Researchers screened over 5 million compounds to find new Alzheimer's disease treatments targeting CDK5. Two compounds, ZINC6261568 and ZINC14168360, show promise as potential lead compounds for drug development.
Area of Science:
- Neuroscience
- Computational Chemistry
- Drug Discovery
Background:
- Alzheimer's disease (AD) is a complex neurodegenerative disorder linked to amyloid beta plaques and neurofibrillary tangles.
- Cyclin-dependent kinase 5 (CDK5) is a key enzyme in tau phosphorylation, a process implicated in AD pathogenesis.
Purpose of the Study:
- To identify novel small molecules that inhibit CDK5 activity for potential Alzheimer's disease treatment.
- To evaluate the drug-likeness and binding affinity of identified compounds through computational methods.
Main Methods:
- High-throughput virtual screening of over 5.3 million compounds against CDK5.
- Pharmacokinetic analysis and redocking simulations using Autodock Vina and Autodock.
- Molecular dynamics (MD) simulations and binding free energy calculations for lead compound validation.
Main Results:
- Screening identified 392 potential inhibitors, which were filtered using pharmacokinetic descriptors.
- Four compounds underwent 100 ns MD simulations, with ZINC6261568 and ZINC14168360 showing significant binding affinity.
- Binding free energy calculations indicated strong interactions for ZINC6261568 (-129.50 kJ/mol) and ZINC14168360 (-191.16 kJ/mol) with CDK5.
Conclusions:
- ZINC6261568 and ZINC14168360 demonstrate potential as effective lead compounds for targeting CDK5 in Alzheimer's disease.
- The study highlights the efficacy of computational approaches in identifying novel therapeutic candidates for neurodegenerative diseases.
More Related Videos
11:44Cellular Membrane Affinity Chromatography Columns to Identify Specialized Plant Metabolites Interacting with Immobilized Tropomyosin Kinase Receptor B
Published on: January 19, 2022
09:49In Vitro Assay for Studying the Aggregation of Tau Protein and Drug Screening
Published on: November 20, 2018