Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors |
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Authors: | Petr Dobeš Jindřich Fanfrlík Jan Řezáč Michal Otyepka Pavel Hobza |
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Institution: | 1.Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science,Palacky University,Olomouc,Czech Republic;2.Institute of Organic Chemistry and Biochemistry,Academy of Sciences of the Czech Republic and Center for Biomolecules and Complex Molecular Systems,Prague 6,Czech Republic;3.Center of Molecular Biology and Gene Therapy, Department of Internal Medicine–Hematooncology,University Hospital Brno,Brno,Czech Republic |
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Abstract: | 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. |
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