title: Quantum mechanical scoring: structural and energetic insights into cyclin-dependent kinase 2 inhibition by pyrazolo[1,5-a]pyrimidines.
abstract: A quantum mechanics (QM)-based scoring function has been applied to complexes of cyclin-dependent kinase 2 (CDK2) and thirty-one pyrazolo[1,5-a]pyrimidine-based inhibitors and their bioisosteres. A hybrid three-layer QM/MM setup (DFT-D/PM6-D3H4X/AMBER in generalized Born solvent) was used here for the first time as an extension of our previous full QM and SQM/MM (SQM means semiempirical QM) approaches. Two approaches to obtain the structures of the CDK2/inhibitor complexes were examined: i) building the modifications from one X-ray structure available coupled with a conformational search and ii) docking the compounds into CDK2. The QM-based scoring entailed a QM/SQM/MM optimization followed by calculations of the binding scores which were subsequently correlated with the experimental binding free energies. The correlation for the building protocol was good (r(2) = 0.64, predictive index = 0.81), whereas the docking approach failed. A decomposition of the interaction energies to ligand fragments enabled us to rationalize the differences in the binding affinities. In conclusion, we have developed and refined a QM-based scoring protocol and successfully applied it to reproduce the binding affinities in congeneric series of CDK2 inhibitors and to rationalize their potency. We thus propose that such a tool can be used in computer-aided rational drug design.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, v.v.i. and Gilead Sciences and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, Prague 6, Czech Republic.
authors.forename: Pathik S
authors.initials: PS
authors.lastname: Brahmkshatriya
authors.forename: Petr
authors.initials: P
authors.lastname: Dobeš
authors.forename: Jindrich
authors.initials: J
authors.lastname: Fanfrlik
authors.forename: Jan
authors.initials: J
authors.lastname: Rezáç
authors.forename: Kamil
authors.initials: K
authors.lastname: Paruch
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bronowska
authors.forename: Martin
authors.initials: M
authors.lastname: Lepšík
authors.forename: Pavel
authors.initials: P
authors.lastname: Hobza
mesh_terms: D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; C527752:pyrazolo(1,5-a)pyrimidine; D051357:Cyclin-Dependent Kinase 2