The Inhibitors of CDK4/6 from a Library of Marine Compound Database: A Pharmacophore, ADMET, Molecular Docking and
Lianxiang Luo1,2,3, Qu Wang4, Yinglin Liao4
1The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China.
Background:
CDK4/6 (Cyclin-dependent kinases 4/6) are the key promoters of cell cycle transition from G1 phase to S phase. Thus, selective inhibition of CDK4/6 is a promising cancer treatment.
Methods:
A total of 52,765 marine natural products were screened for CDK4/6. To screen out better natural compounds, pharmacophore models were first generated, then the absorption, distribution, metabolism, elimination, and toxicity (ADMET) were tested, followed by molecular docking. Finally, molecular dynamics simulation was carried out to verify the binding characteristics of the selected compounds.
Results:
Eighty-seven marine small molecules were screened based on the pharmacophore model. Then, compounds 41369 and 50843 were selected according to the ADMET and molecular docking score for further kinetic simulation evaluation. Finally, through molecular dynamics analysis, it was confirmed that compound 50843 maintained a stable conformation with the target protein, so it has the opportunity to become an inhibitor of CDK4/6.
Conclusion:
Through structure-based pharmacophore modeling, ADMET, the molecular docking method and molecular dynamics (MD) simulation, marine natural compound 50843 was proposed as a promising marine inhibitor of CDK4/6.
Insights
Marine natural compound 50843 shows promise as a CDK4/6 inhibitor. This discovery resulted from screening over 52,000 compounds using computational methods for cancer treatment development.
Area of Science:
- Marine natural products
- Drug discovery
- Computational chemistry
Background:
- Cyclin-dependent kinases 4/6 (CDK4/6) are crucial for cell cycle progression.
- Targeting CDK4/6 is a viable strategy for cancer therapy.
Purpose of the Study:
- To identify novel marine natural products as potential CDK4/6 inhibitors.
- To leverage computational techniques for efficient screening and validation.
Main Methods:
- Structure-based pharmacophore modeling of CDK4/6.
- Screening of a large marine natural product library (52,765 compounds).
- Absorption, Distribution, Metabolism, Elimination, and Toxicity (ADMET) prediction, molecular docking, and molecular dynamics simulations.
Main Results:
- Eighty-seven marine small molecules were initially identified via pharmacophore modeling.
- Compounds 41369 and 50843 were selected based on ADMET and docking scores.
- Molecular dynamics confirmed stable binding of compound 50843 to the target protein.
Conclusions:
- Marine natural compound 50843 is a promising candidate for CDK4/6 inhibition.
- Integrated computational approaches facilitate the discovery of novel therapeutic agents.
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