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

0476134 - ÚOCHB 2018 RIV DE eng J - Journal Article
Nekardová, Michaela - Vymětalová, Ladislava - Khirsariya, P. - Kováčová, S. - Hylsová, M. - Jorda, Radek - Kryštof, Vladimír - Fanfrlík, Jindřich - Hobza, Pavel - Paruch, K.
Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles.
ChemPhysChem. Roč. 18, č. 7 (2017), s. 785-795. ISSN 1439-4235. E-ISSN 1439-7641
R&D Projects: GA ČR(CZ) GBP208/12/G016; GA ČR(CZ) GA15-15264S
Institutional support: RVO:61388963 ; RVO:61389030
Keywords : computational chemistry * enzymes * protein-inhibitor interactions * purine bioisosteres * scaffold hopping
OECD category: Physical chemistry
Impact factor: 2.947, year: 2017

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.
Permanent Link: http://hdl.handle.net/11104/0272666