Exploring Natural Compounds as Potential CDK4 Inhibitors for Therapeutic Intervention in Neurodegenerative Diseases
Neetu Rani1, Pravir Kumar2,3
1Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Bawana Road, Delhi, 110042, India.
Abstract:
CDK4 is a member of the serine-threonine kinase family, which has been found to be overexpressed in a plethora of studies related to neurodegenerative diseases. CDK4 is one of the most validated therapeutic targets for neurodegenerative diseases. Hence, the discovery of potent inhibitors of CDK4 is a promising candidate in the drug discovery field. Firstly, the reference drug Palbociclib was identified from the available literature as a potential candidate against target CDK4. In the present study, the Collection of Open Natural Products (COCONUT) database was accessed for determining potential CDK4 inhibitors using computational approaches based on the Tanimoto algorithm for similarity with the target drug, i.e., Palbociclib. The potential candidates were analyzed using SWISSADME, and the best candidates were filtered based on Lipinski's Rule of 5, Brenk, blood-brain barrier permeability, and Pains parameter. Further, the molecular docking protocol was accessed for the filtered compounds to anticipate the CDK4-ligand binding score, which was validated by the fastDRH web-based server. Based on the best docking score so obtained, the best four natural compounds were chosen for further molecular dynamic simulation to assess their stability with CDK4. In this study, two natural products, with COCONUT Database compound ID-CNP0396493 and CNP0070947, have been identified as the most suitable candidates for neuroprotection.
Insights
Two natural compounds show promise as CDK4 inhibitors for neurodegenerative diseases. These findings offer potential new therapeutic avenues for conditions like Alzheimer
Area of Science:
- Pharmacology
- Computational Chemistry
- Neuroscience
Background:
- Cyclin-dependent kinase 4 (CDK4) is implicated in neurodegenerative diseases.
- CDK4 is a validated therapeutic target for these conditions.
- Developing potent CDK4 inhibitors is crucial for drug discovery.
Purpose of the Study:
- To identify novel natural product inhibitors of CDK4.
- To screen the COCONUT database for compounds similar to Palbociclib.
- To evaluate potential CDK4 inhibitors using computational methods.
Main Methods:
- Virtual screening of the COCONUT database using Tanimoto similarity to Palbociclib.
- ADMET property prediction using SWISSADME, Lipinski's Rule of 5, and Brenk parameters.
- Molecular docking and dynamic simulations to assess binding affinity and stability with CDK4.
Main Results:
- Two natural compounds (CNP0396493 and CNP0070947) were identified as potent CDK4 inhibitors.
- These compounds demonstrated favorable pharmacokinetic properties and blood-brain barrier permeability.
- Molecular dynamics simulations confirmed the stability of the CDK4-ligand complexes.
Conclusions:
- Natural products CNP0396493 and CNP0070947 are promising candidates for neuroprotection.
- These compounds represent potential therapeutic agents for neurodegenerative diseases.
- Further research is warranted to explore their efficacy and safety in preclinical models.
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