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The Inhibitors of CDK4/6 from a Library of Marine Compound Database: A Pharmacophore, ADMET, Molecular Docking and Molecular Dynamics Study

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 c...

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Autores principales: Luo, Lianxiang, Wang, Qu, Liao, Yinglin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144134/
https://www.ncbi.nlm.nih.gov/pubmed/35621970
http://dx.doi.org/10.3390/md20050319
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author Luo, Lianxiang
Wang, Qu
Liao, Yinglin
author_facet Luo, Lianxiang
Wang, Qu
Liao, Yinglin
author_sort Luo, Lianxiang
collection PubMed
description 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.
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spelling pubmed-91441342022-05-29 The Inhibitors of CDK4/6 from a Library of Marine Compound Database: A Pharmacophore, ADMET, Molecular Docking and Molecular Dynamics Study Luo, Lianxiang Wang, Qu Liao, Yinglin Mar Drugs Article 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. MDPI 2022-05-12 /pmc/articles/PMC9144134/ /pubmed/35621970 http://dx.doi.org/10.3390/md20050319 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Luo, Lianxiang
Wang, Qu
Liao, Yinglin
The Inhibitors of CDK4/6 from a Library of Marine Compound Database: A Pharmacophore, ADMET, Molecular Docking and Molecular Dynamics Study
title The Inhibitors of CDK4/6 from a Library of Marine Compound Database: A Pharmacophore, ADMET, Molecular Docking and Molecular Dynamics Study
title_full The Inhibitors of CDK4/6 from a Library of Marine Compound Database: A Pharmacophore, ADMET, Molecular Docking and Molecular Dynamics Study
title_fullStr The Inhibitors of CDK4/6 from a Library of Marine Compound Database: A Pharmacophore, ADMET, Molecular Docking and Molecular Dynamics Study
title_full_unstemmed The Inhibitors of CDK4/6 from a Library of Marine Compound Database: A Pharmacophore, ADMET, Molecular Docking and Molecular Dynamics Study
title_short The Inhibitors of CDK4/6 from a Library of Marine Compound Database: A Pharmacophore, ADMET, Molecular Docking and Molecular Dynamics Study
title_sort inhibitors of cdk4/6 from a library of marine compound database: a pharmacophore, admet, molecular docking and molecular dynamics study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144134/
https://www.ncbi.nlm.nih.gov/pubmed/35621970
http://dx.doi.org/10.3390/md20050319
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