Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines

0475922 - ÚOCHB 2018 RIV FR eng J - Journal Article
Hylsová, M. - Carbain, B. - Fanfrlík, Jindřich - Musilová, L. - Haldar, Susanta - Köprülüoglu, Cemal - Ajani, Haresh - Brahmkshatriya, Pathik - Jorda, Radek - Kryštof, Vladimír - Hobza, Pavel - Echalier, A. - Paruch, K. - Lepšík, Martin
Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines.
European Journal of Medicinal Chemistry. Roč. 126, Jan 27 (2017), s. 1118-1128. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA ČR(CZ) GA15-15264S; GA ČR(CZ) GBP208/12/G016
Institutional support: RVO:61388963 ; RVO:61389030
Keywords : cyclin-dependent kinase 2 * ATP-competitive type I inhibitors * pyrazolo[1,5-a]pyrimidine * quantum mechanical scoring * protein-ligand binding * molecular dynamics
OECD category: Organic chemistry
Impact factor: 4.816, year: 2017

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.
Permanent Link: http://hdl.handle.net/11104/0272505