Journal of Computer-Aided Molecular Design

, Volume 25, Issue 3, pp 223–235 | Cite as

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

  • Petr Dobeš
  • Jindřich Fanfrlík
  • Jan Řezáč
  • Michal Otyepka
  • Pavel Hobza


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.


CDK2 Semiempirical quantum mechanical method PM6-DH2 Non-covalent interaction Scoring function Drug design 



Cyclin-dependent kinase 2


Molecular mechanics


Quantum mechanics


Semiempirical quantum mechanics


Protein (P)–inhibitor (I) complex



This work was a part of research project No. Z40550506 of the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic and was supported by Grants No. LC512 and MSM6198959216 from the Ministry of Education, Youth and Sports of the Czech Republic. The support of Praemium Academiae, Academy of Sciences of the Czech Republic, awarded to P.H. in 2007, is also acknowledged. It was also supported by The Czech Science Foundation (P208/11/0295). This work was supported by the Operational Program Research and Development for Innovations—European Social Fund (CZ.1.05/2.1.00/03.0058).

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Authors and Affiliations

  1. 1.Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of SciencePalacký UniversityOlomoucCzech Republic
  2. 2.Institute of Organic Chemistry and BiochemistryAcademy of Sciences of the Czech Republic and Center for Biomolecules and Complex Molecular SystemsPrague 6Czech Republic
  3. 3.Center of Molecular Biology and Gene Therapy, Department of Internal Medicine–HematooncologyUniversity Hospital BrnoBrnoCzech Republic

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