We present comprehensive testing of solvent representation in quantum mechanics (QM)-based scoring of protein-ligand affinities. To this aim, we prepared 21 new inhibitors of cyclin-dependent kinase 2 (CDK2) with the pyrazolo[1,5-a]pyrimidine core, whose activities spanned three orders of magnitude. The crystal structure of a potent inhibitor bound to the active CDK2/cyclin A complex revealed that the biphenyl substituent at position 5 of the pyrazolo[1,5-a]pyrimidine scaffold was located in a previously unexplored pocket and that six water molecules resided in the active site. Using molecular dynamics, protein-ligand interactions and active-site water H-bond networks as well as thermodynamics were probed. Thereafter, all the inhibitors were scored by the QM approach utilizing the COSMO implicit solvent model. Such a standard treatment failed to produce a correlation with the experiment (R(2) = 0.49). However, the addition of the active-site waters resulted in significant improvement (R(2) = 0.68). The activities of the compounds could thus be interpreted by taking into account their specific noncovalent interactions with CDK2 and the active-site waters. In summary, using a combination of several experimental and theoretical approaches we demonstrate that the inclusion of explicit solvent effects enhance QM/COSMO scoring to produce a reliable structure-activity relationship with physical insights. More generally, this approach is envisioned to contribute to increased accuracy of the computational design of novel inhibitors.

Centre de Biochimie Structurale CNRS UMR 5048 UM INSERM U 1054 29 rue de Navacelles 34090 Montpellier France

Department of Chemistry CZ Openscreen Masaryk University Kamenice 5 625 00 Brno Czech Republic

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic v v i Flemingovo nam 2 166 10 Prague 6 Czech Republic

International Clinical Research Center St Anne's University Hospital Brno Pekařská 53 656 91 Brno Czech Republic

Laboratory of Growth Regulators Faculty of Science Palacký University Institute of Experimental Botany Šlechtitelů 27 783 71 Olomouc Czech Republic

Regional Center of Advanced Technologies and Materials Department of Physical Chemistry Palacký University 771 46 Olomouc Czech Republic

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