Molecular basis of differential selectivity of cyclobutyl-substituted imidazole inhibitors against CDKs: insights for rational drug design.

Cyclin-dependent kinases (CDKs) belong to the CMGC subfamily of protein kinases and play crucial roles in eukaryotic cell division cycle. At least seven different CDKs have been reported to be implicated in the cell cycle regulation in vertebrates. These CDKs are highly homologous and contain a cons...

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Autores principales:	Soumya Lipsa Rath, Sanjib Senapati
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7bde895fa937444fbe51a94c8a167a16
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spelling	oai:doaj.org-article:7bde895fa937444fbe51a94c8a167a162021-11-18T08:55:23ZMolecular basis of differential selectivity of cyclobutyl-substituted imidazole inhibitors against CDKs: insights for rational drug design.1932-620310.1371/journal.pone.0073836https://doaj.org/article/7bde895fa937444fbe51a94c8a167a162013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24058495/?tool=EBIhttps://doaj.org/toc/1932-6203Cyclin-dependent kinases (CDKs) belong to the CMGC subfamily of protein kinases and play crucial roles in eukaryotic cell division cycle. At least seven different CDKs have been reported to be implicated in the cell cycle regulation in vertebrates. These CDKs are highly homologous and contain a conserved catalytic core. This makes the design of inhibitors specific for a particular CDK difficult. There is, however, growing need for CDK5 specific inhibitors to treat various neurodegenerative diseases. Recently, cis-substituted cyclobutyl-4-aminoimidazole inhibitors have been identified as potent CDK5 inhibitors that gave up to 30-fold selectivity over CDK2. Available IC50 values also indicate a higher potency of this class of inhibitors over commercially available drugs, such as roscovitine. To understand the molecular basis of higher potency and selectivity of these inhibitors, here, we present molecular dynamics simulation results of CDK5/p25 and CDK2/CyclinE complexed with a series of cyclobutyl-substituted imidazole inhibitors and roscovitine. The atomic details of the stereospecificity and selectivity of these inhibitors are obtained from energetics and binding characteristics to the CDK binding pocket. The study not only complements the experimental findings, but also provides a wealth of detailed information that could help the structure-based drug designing processes.Soumya Lipsa RathSanjib SenapatiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e73836 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Soumya Lipsa Rath Sanjib Senapati Molecular basis of differential selectivity of cyclobutyl-substituted imidazole inhibitors against CDKs: insights for rational drug design.
description	Cyclin-dependent kinases (CDKs) belong to the CMGC subfamily of protein kinases and play crucial roles in eukaryotic cell division cycle. At least seven different CDKs have been reported to be implicated in the cell cycle regulation in vertebrates. These CDKs are highly homologous and contain a conserved catalytic core. This makes the design of inhibitors specific for a particular CDK difficult. There is, however, growing need for CDK5 specific inhibitors to treat various neurodegenerative diseases. Recently, cis-substituted cyclobutyl-4-aminoimidazole inhibitors have been identified as potent CDK5 inhibitors that gave up to 30-fold selectivity over CDK2. Available IC50 values also indicate a higher potency of this class of inhibitors over commercially available drugs, such as roscovitine. To understand the molecular basis of higher potency and selectivity of these inhibitors, here, we present molecular dynamics simulation results of CDK5/p25 and CDK2/CyclinE complexed with a series of cyclobutyl-substituted imidazole inhibitors and roscovitine. The atomic details of the stereospecificity and selectivity of these inhibitors are obtained from energetics and binding characteristics to the CDK binding pocket. The study not only complements the experimental findings, but also provides a wealth of detailed information that could help the structure-based drug designing processes.
format	article
author	Soumya Lipsa Rath Sanjib Senapati
author_facet	Soumya Lipsa Rath Sanjib Senapati
author_sort	Soumya Lipsa Rath
title	Molecular basis of differential selectivity of cyclobutyl-substituted imidazole inhibitors against CDKs: insights for rational drug design.
title_short	Molecular basis of differential selectivity of cyclobutyl-substituted imidazole inhibitors against CDKs: insights for rational drug design.
title_full	Molecular basis of differential selectivity of cyclobutyl-substituted imidazole inhibitors against CDKs: insights for rational drug design.
title_fullStr	Molecular basis of differential selectivity of cyclobutyl-substituted imidazole inhibitors against CDKs: insights for rational drug design.
title_full_unstemmed	Molecular basis of differential selectivity of cyclobutyl-substituted imidazole inhibitors against CDKs: insights for rational drug design.
title_sort	molecular basis of differential selectivity of cyclobutyl-substituted imidazole inhibitors against cdks: insights for rational drug design.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/7bde895fa937444fbe51a94c8a167a16
work_keys_str_mv	AT soumyalipsarath molecularbasisofdifferentialselectivityofcyclobutylsubstitutedimidazoleinhibitorsagainstcdksinsightsforrationaldrugdesign AT sanjibsenapati molecularbasisofdifferentialselectivityofcyclobutylsubstitutedimidazoleinhibitorsagainstcdksinsightsforrationaldrugdesign
_version_	1718421147548123136

Molecular basis of differential selectivity of cyclobutyl-substituted imidazole inhibitors against CDKs: insights for rational drug design.

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