Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors

• Published in: Journal of computer-aided molecular design Vol. 25; no. 3; pp. 223 - 235
• Main Authors: Dobeš, Petr, Fanfrlík, Jindřich, Řezáč, Jan, Otyepka, Michal, Hobza, Pavel
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01-03-2011; Springer Nature B.V
• Subjects: Animal Anatomy; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Correlation; Correlation analysis; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-dependent kinases; Deformation; Design engineering; Dispersion; Drug Design; Enthalpy; Entropy; Histology; Humans; Inhibitors; Ligands; Mathematical analysis; Mathematical models; Models, Molecular; Morphology; Physical Chemistry; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Quantum physics; Quantum Theory; Scoring; Thermodynamics; Scoring function; Drug design; Non-covalent interaction; PM6-DH2; Semiempirical quantum mechanical method; CDK2
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-011-9413-5

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.