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

0360708 - ÚOCHB 2012 RIV NL eng J - Journal Article
Dobeš, Petr - Fanfrlík, Jindřich - Řezáč, Jan - Otyepka, M. - Hobza, Pavel
Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors.
Journal of Computer-Aided Molecular Design. Roč. 25, č. 3 (2011), s. 223-235. ISSN 0920-654X. E-ISSN 1573-4951
R&D Projects: GA MŠMT LC512; GA ČR GAP208/11/0295
Grant - others:European Social Fund(XE) CZ.1.05/2.1.00/03.0058
Institutional research plan: CEZ:AV0Z40550506
Keywords : CDK2 * semiempirical quantum mechanical method PM6-DH2 * drug design
Subject RIV: CF - Physical ; Theoretical Chemistry
Impact factor: 3.386, year: 2011

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 Ki) were found for bare interaction enthalpy (r2 = 0.87) and interaction enthalpy corrected for ligand desolvation and deformation energies (r2 = 0.77); when the entropic term was considered, however, the correlation becomes worse but still acceptable.
Permanent Link: http://hdl.handle.net/11104/0198195