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-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.

Department of Chemistry CZ Openscreen Masaryk University Kamenice 5 62500 Brno Czech Republic

Faculty of Mathematics and Physics Charles University Prague Ke Karlovu 3 Prague 2 121 16 Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 166 10 Prague 6 Czech Republic

International Center for Clinical Research St Anne's University Hospital Brno Pekařská 53 656 91 Brno Czech Republic

Laboratory of Growth Regulators Faculty of Science of Palacky University and Institute of Experimental Botany of the Czech Academy of Sciences Šlechtitelů 27 78371 Olomouc Czech Republic

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