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

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Authors

NEKARDOVÁ Michaela VYMĚTALOVÁ Ladislava KHIRSARIYA Prashant Kumar KOVÁČOVÁ Silvia HYLSOVÁ Michaela JORDA Radek KRYŠTOF Vladimír FANFRLÍK Jindřich HOBZA Pavel PARUCH Kamil

Year of publication 2017
Type Article in Periodical
Magazine / Source ChemPhysChem
MU Faculty or unit

Faculty of Science

Citation
Web odkaz na publikaci
Doi http://dx.doi.org/10.1002/cphc.201601319
Field Organic chemistry
Keywords computational chemistry; enzymes; protein– inhibitor interactions; purine bioisosteres; scaffold hopping
Description 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.
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