Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles
Language English Country Germany Media print-electronic
Document type Journal Article
- Keywords
- computational chemistry, enzymes, protein-inhibitor interactions, purine bioisosteres, scaffold hopping,
- MeSH
- Cyclin-Dependent Kinase 2 antagonists & inhibitors chemistry MeSH
- Heterocyclic Compounds chemistry pharmacology MeSH
- Protein Kinase Inhibitors chemistry pharmacology MeSH
- Crystallography, X-Ray MeSH
- Quantum Theory * MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Purines chemistry pharmacology MeSH
- Roscovitine MeSH
- Static Electricity MeSH
- Thermodynamics MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Cyclin-Dependent Kinase 2 MeSH
- Heterocyclic Compounds MeSH
- Protein Kinase Inhibitors MeSH
- Purines MeSH
- Roscovitine MeSH
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.
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