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Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles
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SYSNO ASEP 0476134 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles Tvůrce(i) Nekardová, Michaela (UOCHB-X) RID
Vymětalová, Ladislava (UEB-Q)
Khirsariya, P. (CZ)
Kováčová, S. (CZ)
Hylsová, M. (CZ)
Jorda, Radek (UEB-Q) ORCID, RID
Kryštof, Vladimír (UEB-Q) RID, ORCID
Fanfrlík, Jindřich (UOCHB-X) RID, ORCID
Hobza, Pavel (UOCHB-X) RID, ORCID
Paruch, K. (CZ)Zdroj.dok. ChemPhysChem. - : Wiley - ISSN 1439-4235
Roč. 18, č. 7 (2017), s. 785-795Poč.str. 11 s. Jazyk dok. eng - angličtina Země vyd. DE - Německo Klíč. slova computational chemistry ; enzymes ; protein-inhibitor interactions ; purine bioisosteres ; scaffold hopping Vědní obor RIV CF - Fyzikální chemie a teoretická chemie Obor OECD Physical chemistry CEP GBP208/12/G016 GA ČR - Grantová agentura ČR GA15-15264S GA ČR - Grantová agentura ČR Institucionální podpora UOCHB-X - RVO:61388963 ; UEB-Q - RVO:61389030 UT WOS 000402711100009 EID SCOPUS 85013293315 DOI 10.1002/cphc.201601319 Anotace The structural basis for the interaction of roscovitine and analogues containing 13 different bioisosteric central heterocycles with the enzyme cyclin-dependent kinase 2 (CDK2) is elucidated. 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-em-pirical 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. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Rok sběru 2018
Počet záznamů: 1