Molecular dynamic simulations give insight into the mechanism of binding between 2-aminothiazole inhibitors and CDK5

Wang, Wei; Cao, Xiaoning; Zhu, Xiaolei; Gu, Yongliang

doi:10.1007/s00894-013-1815-y

Cited by 4 publications

(2 citation statements)

References 61 publications

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“…These results are in agreement with the binding mechanism of cyclobutyl-substituted imidazole inhibitors with CDKs[54]. However, for the 2-aminothiazole inhibitors[55], the van der Waals component is the mainly contribution binding.In order to reveal how the electrostatic interactions affect the binding affinity of A1, A2 and A3 with CDK5, the hydrogen bond interactions are carefully analyzed in terms ofFig. 6.…”

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confidence: 92%

Binding mechanism of CDK5 with roscovitine derivatives based on molecular dynamics simulations and MM/PBSA methods

Keke

Wang

Yang

et al. 2016

Journal of Molecular Graphics and Modelling

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Roscovitine derivatives are potent inhibitors of cyclin-dependent kinase 5 (CDK5), but they exhibit different activities, which has not been understood clearly up to now. On the other hand, the task of drug design is difficult because of the fuzzy binding mechanism. In this context, the methods of molecular docking, molecular dynamics (MD) simulation, and binding free energy analysis are applied to investigate and reveal the detailed binding mechanism of four roscovitine derivatives with CDK5. The electrostatic and van der Waals interactions of the four inhibitors with CDK5 are analyzed and discussed. The calculated binding free energies in terms of MM-PBSA method are consistent with experimental ranking of inhibitor effectiveness for the four inhibitors. The hydrogen bonds of the inhibitors with Cys83 and Lys33 can stabilize the inhibitors in binding sites. The van der Waals interactions, especially the pivotal contacts with Ile10 and Leu133 have larger contributions to the binding free energy and play critical roles in distinguishing the variant bioactivity of four inhibitors. In terms of binding mechanism of the four inhibitors with CDK5 and energy contribution of fragments of each inhibitor, two new CDK5 inhibitors are designed and have stronger inhibitory potency.

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confidence: 92%

Binding mechanism of CDK5 with roscovitine derivatives based on molecular dynamics simulations and MM/PBSA methods

Keke

Wang

Yang

et al. 2016

Journal of Molecular Graphics and Modelling

Self Cite

View full text Add to dashboard Cite

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“…The Ile 10 residue was earlier found to be an essential residue responsible for biological activity based on molecular dynamics study. 29 To design new molecules with improved activity/selectivity, one has to consider the above requisite structural features, while trying with recommended different scaffolds (for e.g., different ring structures or branched structures at R 1 position) at various positions on similar backbones and then can predict the activity or selectivity values using reported QSAR models. Further, the newly designed molecules can be docked to the CDK5/p25 enzyme to notice the changes in interactions with active site residues and docking scores due to newly added structural features.…”

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confidence: 99%