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@article{1383715,
author = {Nekardová, Michaela and Vymětalová, Ladislava and Khirsariya, Prashant Kumar and Kováčová, Silvia and Hylsová, Michaela and Jorda, Radek and Kryštof, Vladimír and Fanfrlík, Jindřich and Hobza, Pavel and Paruch, Kamil},
article_location = {WEINHEIM},
article_number = {7},
doi = {http://dx.doi.org/10.1002/cphc.201601319},
keywords = {computational chemistry; enzymes; protein– inhibitor interactions; purine bioisosteres; scaffold hopping},
language = {eng},
issn = {1439-4235},
journal = {ChemPhysChem},
title = {Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles},
url = {http://onlinelibrary.wiley.com/doi/10.1002/cphc.201601319/abstract},
volume = {18},
year = {2017}
}
TY - JOUR
ID - 1383715
AU - Nekardová, Michaela - Vymětalová, Ladislava - Khirsariya, Prashant Kumar - Kováčová, Silvia - Hylsová, Michaela - Jorda, Radek - Kryštof, Vladimír - Fanfrlík, Jindřich - Hobza, Pavel - Paruch, Kamil
PY - 2017
TI - Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles
JF - ChemPhysChem
VL - 18
IS - 7
SP - 785-795
EP - 785-795
PB - Wiley
SN - 14394235
KW - computational chemistry
KW - enzymes
KW - protein– inhibitor interactions
KW - purine bioisosteres
KW - scaffold hopping
UR - http://onlinelibrary.wiley.com/doi/10.1002/cphc.201601319/abstract
L2 - http://onlinelibrary.wiley.com/doi/10.1002/cphc.201601319/abstract
N2 - Although all the central scaffolds are very similar to the purine core of roscovitine, the experimentally determined IC50 values of the inhibitors span three orders of magnitude. By using an extensive computational chemistry approach, the affinities of the inhibitors to CDK2 are determined as calculated binding scores of complexes of the inhibitors with the protein. The interactions of the inhibitors with CDK2 are computationally described by using a hybrid quantum mechanics semi empirical quantum mechanics method QM SQM, which combines the DFT D method for the QM part and the PM6 D3H4X method for the SQM part. The solvent effect is described by the COSMO implicit solvation model at the SQM level for the whole system. The contributions of the scaffolds and the individual substituents, quantified and evaluated in relation to conformations of optimized protein inhibitor complexes, are found not to be simply additive. The inhibitory activity of the selected candidates, including two newly prepared compounds, is tested against CDK2. The results of the calculations are in close agreement with the experimental data.
ER -
NEKARDOVÁ, Michaela, Ladislava VYMĚTALOVÁ, Prashant Kumar KHIRSARIYA, Silvia KOVÁČOVÁ, Michaela HYLSOVÁ, Radek JORDA, Vladimír KRYŠTOF, Jindřich FANFRLÍK, Pavel HOBZA and Kamil PARUCH. Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles. \textit{ChemPhysChem}. WEINHEIM: Wiley, 2017, vol.~18, No~7, p.~785-795. ISSN~1439-4235. Available from: https://dx.doi.org/10.1002/cphc.201601319.
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