Structural Basis of the Interaction of Cyclin-Dependent Kinase
2 with Roscovitine and Its Analogues Having Bioisosteric
Central Heterocycles

J 2017

Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles

NEKARDOVÁ, Michaela, Ladislava VYMĚTALOVÁ, Prashant Kumar KHIRSARIYA, Silvia KOVÁČOVÁ, Michaela HYLSOVÁ et. al.

Basic information

Original name

Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles

Authors

NEKARDOVÁ, Michaela (203 Czech Republic), Ladislava VYMĚTALOVÁ (203 Czech Republic), Prashant Kumar KHIRSARIYA (356 India, belonging to the institution), Silvia KOVÁČOVÁ (703 Slovakia, belonging to the institution), Michaela HYLSOVÁ (203 Czech Republic, belonging to the institution), Radek JORDA (203 Czech Republic), Vladimír KRYŠTOF (203 Czech Republic), Jindřich FANFRLÍK (203 Czech Republic), Pavel HOBZA (203 Czech Republic) and Kamil PARUCH (203 Czech Republic, guarantor, belonging to the institution)

Edition

ChemPhysChem, WEINHEIM, Wiley, 2017, 1439-4235

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10401 Organic chemistry

Country of publisher

Germany

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

odkaz na publikaci

Impact factor

Impact factor: 2.947

RIV identification code

RIV/00216224:14310/17:00097036

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1002/cphc.201601319

UT WoS

000402711100009

Keywords in English

computational chemistry; enzymes; protein– inhibitor interactions; purine bioisosteres; scaffold hopping

Abstract

V originále

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.

Links

LM2015063, research and development project

Name: Národní infrastruktura chemické biologie (Acronym: CZ-OPENSCREEN)

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

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. ChemPhysChem. WEINHEIM: Wiley, 2017, vol. 18, No 7, p. 785-795. ISSN 1439-4235. Available from: https://dx.doi.org/10.1002/cphc.201601319.

@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.

Detailed Information on Publication Record