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Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy

Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibit...

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Autores principales: Mohammad, Taj, Batra, Sagar, Dahiya, Rashmi, Baig, Mohammad Hassan, Rather, Irfan Ahmad, Dong, Jae-June, Hassan, Imtaiyaz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943647/
https://www.ncbi.nlm.nih.gov/pubmed/31847444
http://dx.doi.org/10.3390/molecules24244589
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author Mohammad, Taj
Batra, Sagar
Dahiya, Rashmi
Baig, Mohammad Hassan
Rather, Irfan Ahmad
Dong, Jae-June
Hassan, Imtaiyaz
author_facet Mohammad, Taj
Batra, Sagar
Dahiya, Rashmi
Baig, Mohammad Hassan
Rather, Irfan Ahmad
Dong, Jae-June
Hassan, Imtaiyaz
author_sort Mohammad, Taj
collection PubMed
description Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors. First, we retrieved all compounds from the PubChem database having at least 90% structural similarity with the known CDK2 inhibitors. The selected compounds were subjected to structure-based molecular docking studies to investigate their pattern of interaction and estimate their binding affinities with CDK2. Selected compounds were further filtered out based on their physicochemical and ADMET properties. Detailed interaction analysis revealed that selected compounds interact with the functionally important residues of the active site pocket of CDK2. All-atom molecular dynamics simulation was performed to evaluate conformational changes, stability and the interaction mechanism of CDK2 in-complex with the selected compound. We found that binding of 6-N,6-N-dimethyl-9-(2-phenylethyl)purine-2,6-diamine stabilizes the structure of CDK2 and causes minimal conformational change. Finally, we suggest that the compound (PubChem ID 101874157) would be a promising scaffold to be further exploited as a potential inhibitor of CDK2 for therapeutic management of cancer after required validation.
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spelling pubmed-69436472020-01-10 Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy Mohammad, Taj Batra, Sagar Dahiya, Rashmi Baig, Mohammad Hassan Rather, Irfan Ahmad Dong, Jae-June Hassan, Imtaiyaz Molecules Article Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors. First, we retrieved all compounds from the PubChem database having at least 90% structural similarity with the known CDK2 inhibitors. The selected compounds were subjected to structure-based molecular docking studies to investigate their pattern of interaction and estimate their binding affinities with CDK2. Selected compounds were further filtered out based on their physicochemical and ADMET properties. Detailed interaction analysis revealed that selected compounds interact with the functionally important residues of the active site pocket of CDK2. All-atom molecular dynamics simulation was performed to evaluate conformational changes, stability and the interaction mechanism of CDK2 in-complex with the selected compound. We found that binding of 6-N,6-N-dimethyl-9-(2-phenylethyl)purine-2,6-diamine stabilizes the structure of CDK2 and causes minimal conformational change. Finally, we suggest that the compound (PubChem ID 101874157) would be a promising scaffold to be further exploited as a potential inhibitor of CDK2 for therapeutic management of cancer after required validation. MDPI 2019-12-15 /pmc/articles/PMC6943647/ /pubmed/31847444 http://dx.doi.org/10.3390/molecules24244589 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mohammad, Taj
Batra, Sagar
Dahiya, Rashmi
Baig, Mohammad Hassan
Rather, Irfan Ahmad
Dong, Jae-June
Hassan, Imtaiyaz
Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy
title Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy
title_full Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy
title_fullStr Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy
title_full_unstemmed Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy
title_short Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy
title_sort identification of high-affinity inhibitors of cyclin-dependent kinase 2 towards anticancer therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943647/
https://www.ncbi.nlm.nih.gov/pubmed/31847444
http://dx.doi.org/10.3390/molecules24244589
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