CHA on CDK2: a way to identify the best pharmacophore model for the virtual screening of new inhibitors

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Abstract

Cyclin-dependent kinase-2 (CDK2) is a member of serine/threonine protein kinases family. It plays an important role in the regulation events of the eukaryotic cell division cycle, especially during the G1 to S phase transition. Experimental evidences indicate that excessive expression of CDK2 should cause abnormal cell cycle regulation. Therefore, CDK2 has been considered a potential therapeutic target for cancer therapy. In this work, we used a modelling approach that incorporates flexibility based on extensive MD simulations of protein−ligand complexes into structure-based pharmacophore modeling and virtual screening to identify new CDK2 inhibitors. One-hundred and forty-nine CDK2-inhibitors complexes were submitted to MD simulations to examine the crucial ligand-protein interactions within the complexes. Then we applied the Common Hits Approach (CHA) (1) which uses the set of coordinates saved during MD simulations, and generates for each frame a pharmacophore model. The high number of pharmacophore models resulting from the MD simulation is reduced to a few representative sets of pharmacophore models grouped in a list. This list is used to screen our in-house data for detection of new CDK-2 inhibitors. (1) Wieder, M et al. (2017) Common Hits Approach: Combining Pharmacophore Modeling and Molecular Dynamics Simulations. J. Chem. Inf. Model., 57: 365-385.
Lingua originaleEnglish
Stato di pubblicazionePublished - 2018

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title = "CHA on CDK2: a way to identify the best pharmacophore model for the virtual screening of new inhibitors",
abstract = "Cyclin-dependent kinase-2 (CDK2) is a member of serine/threonine protein kinases family. It plays an important role in the regulation events of the eukaryotic cell division cycle, especially during the G1 to S phase transition. Experimental evidences indicate that excessive expression of CDK2 should cause abnormal cell cycle regulation. Therefore, CDK2 has been considered a potential therapeutic target for cancer therapy. In this work, we used a modelling approach that incorporates flexibility based on extensive MD simulations of protein−ligand complexes into structure-based pharmacophore modeling and virtual screening to identify new CDK2 inhibitors. One-hundred and forty-nine CDK2-inhibitors complexes were submitted to MD simulations to examine the crucial ligand-protein interactions within the complexes. Then we applied the Common Hits Approach (CHA) (1) which uses the set of coordinates saved during MD simulations, and generates for each frame a pharmacophore model. The high number of pharmacophore models resulting from the MD simulation is reduced to a few representative sets of pharmacophore models grouped in a list. This list is used to screen our in-house data for detection of new CDK-2 inhibitors. (1) Wieder, M et al. (2017) Common Hits Approach: Combining Pharmacophore Modeling and Molecular Dynamics Simulations. J. Chem. Inf. Model., 57: 365-385.",
keywords = "cdk2, pharmacophore modelling, virtual screening",
author = "Marco Tutone and Giulia Culletta",
year = "2018",
language = "English",

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TY - CONF

T1 - CHA on CDK2: a way to identify the best pharmacophore model for the virtual screening of new inhibitors

AU - Tutone, Marco

AU - Culletta, Giulia

PY - 2018

Y1 - 2018

N2 - Cyclin-dependent kinase-2 (CDK2) is a member of serine/threonine protein kinases family. It plays an important role in the regulation events of the eukaryotic cell division cycle, especially during the G1 to S phase transition. Experimental evidences indicate that excessive expression of CDK2 should cause abnormal cell cycle regulation. Therefore, CDK2 has been considered a potential therapeutic target for cancer therapy. In this work, we used a modelling approach that incorporates flexibility based on extensive MD simulations of protein−ligand complexes into structure-based pharmacophore modeling and virtual screening to identify new CDK2 inhibitors. One-hundred and forty-nine CDK2-inhibitors complexes were submitted to MD simulations to examine the crucial ligand-protein interactions within the complexes. Then we applied the Common Hits Approach (CHA) (1) which uses the set of coordinates saved during MD simulations, and generates for each frame a pharmacophore model. The high number of pharmacophore models resulting from the MD simulation is reduced to a few representative sets of pharmacophore models grouped in a list. This list is used to screen our in-house data for detection of new CDK-2 inhibitors. (1) Wieder, M et al. (2017) Common Hits Approach: Combining Pharmacophore Modeling and Molecular Dynamics Simulations. J. Chem. Inf. Model., 57: 365-385.

AB - Cyclin-dependent kinase-2 (CDK2) is a member of serine/threonine protein kinases family. It plays an important role in the regulation events of the eukaryotic cell division cycle, especially during the G1 to S phase transition. Experimental evidences indicate that excessive expression of CDK2 should cause abnormal cell cycle regulation. Therefore, CDK2 has been considered a potential therapeutic target for cancer therapy. In this work, we used a modelling approach that incorporates flexibility based on extensive MD simulations of protein−ligand complexes into structure-based pharmacophore modeling and virtual screening to identify new CDK2 inhibitors. One-hundred and forty-nine CDK2-inhibitors complexes were submitted to MD simulations to examine the crucial ligand-protein interactions within the complexes. Then we applied the Common Hits Approach (CHA) (1) which uses the set of coordinates saved during MD simulations, and generates for each frame a pharmacophore model. The high number of pharmacophore models resulting from the MD simulation is reduced to a few representative sets of pharmacophore models grouped in a list. This list is used to screen our in-house data for detection of new CDK-2 inhibitors. (1) Wieder, M et al. (2017) Common Hits Approach: Combining Pharmacophore Modeling and Molecular Dynamics Simulations. J. Chem. Inf. Model., 57: 365-385.

KW - cdk2, pharmacophore modelling, virtual screening

UR - http://hdl.handle.net/10447/350034

M3 - Paper

ER -