Most cited article - PubMed ID 16575928
Interaction energies for the purine inhibitor roscovitine with cyclin-dependent kinase 2: correlated ab initio quantum-chemical, DFT and empirical calculations
A semiempirical quantum mechanical PM6-DH2 method accurately covering the dispersion interaction and H-bonding was used to score fifteen structurally diverse CDK2 inhibitors. The geometries of all the complexes were taken from the X-ray structures and were reoptimised by the PM6-DH2 method in continuum water. The total scoring function was constructed as an estimate of the binding free energy, i.e., as a sum of the interaction enthalpy, interaction entropy and the corrections for the inhibitor desolvation and deformation energies. The applied scoring function contains a clear thermodynamical terms and does not involve any adjustable empirical parameter. The best correlations with the experimental inhibition constants (ln K (i)) were found for bare interaction enthalpy (r (2) = 0.87) and interaction enthalpy corrected for ligand desolvation and deformation energies (r (2) = 0.77); when the entropic term was considered, however, the correlation becomes worse but still acceptable (r (2) = 0.52). The resulting correlation based on the PM6-DH2 scoring function is better than previously published function based on various docking/scoring, SAR studies or advanced QM/MM approach, however, the robustness is limited by number of available experimental data used in the correlation. Since a very similar correlation between the experimental and theoretical results was found also for a different system of the HIV-1 protease, the suggested scoring function based on the PM6-DH2 method seems to be applicable in drug design, even if diverse protein-ligand complexes have to be ranked.
- MeSH
- Cyclin-Dependent Kinase 2 antagonists & inhibitors metabolism MeSH
- Protein Kinase Inhibitors chemistry pharmacology MeSH
- Quantum Theory MeSH
- Humans MeSH
- Ligands MeSH
- Models, Molecular MeSH
- Drug Design * MeSH
- Thermodynamics MeSH
- Protein Binding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- CDK2 protein, human MeSH Browser
- Cyclin-Dependent Kinase 2 MeSH
- Protein Kinase Inhibitors MeSH
- Ligands MeSH
