Exploring Natural Compounds as Potential CDK4 Inhibitors for Therapeutic Intervention in Neurodegenerative Diseases...

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.