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

• Published in: European journal of medicinal chemistry Vol. 126; pp. 1118 - 1128
• Main Authors: Hylsová, Michaela, Carbain, Benoit, Fanfrlík, Jindřich, Musilová, Lenka, Haldar, Susanta, Köprülüoğlu, Cemal, Ajani, Haresh, Brahmkshatriya, Pathik S., Jorda, Radek, Kryštof, Vladimír, Hobza, Pavel, Echalier, Aude, Paruch, Kamil, Lepšík, Martin
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 27.01.2017; Elsevier
• Subjects: ATP-competitive type I inhibitors; Catalytic Domain; Chemistry, Medicinal; Cyclin A - metabolism; Cyclin-dependent kinase 2; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - chemistry; Cyclin-Dependent Kinase 2 - metabolism; Drug Design; Humans; Life Sciences & Biomedicine; Molecular dynamics; Molecular Dynamics Simulation; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Protein-ligand binding; Pyrazolo[1,5-a]pyrimidine; Pyrimidines - chemistry; Pyrimidines - metabolism; Pyrimidines - pharmacology; Quantum mechanical scoring; Quantum Theory; Science & Technology; Solvents - chemistry; Structure-Activity Relationship; Water - chemistry; Water thermodynamics; X-ray crystal structure; Cyclin-dependent kinase 2; Protein-ligand binding; ATP-competitive type I inhibitors; Pyrazolo[1,5-a]pyrimidine; Quantum mechanical scoring; Molecular dynamics; X-ray crystal structure; Water thermodynamics; MOLECULAR-DYNAMICS; ALDOSE REDUCTASE INHIBITION; DRUG DESIGN; CYCLIN-DEPENDENT KINASES; FREE-ENERGY CALCULATIONS; SELECTIVE INHIBITOR; HALOGEN BONDS; FORCE-FIELD; HIV-1 PROTEASE
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.12.023

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 (R2 = 0.49). However, the addition of the active-site waters resulted in significant improvement (R2 = 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. [Display omitted] •The importance of active-site water molecules in QM/COSMO scoring is demonstrated.•21 new pyrazolo[1,5-a]pyrimidine-based inhibitors of CDK 2 are synthesized.•Crystal structure of active CDK2/cyclin A/inhibitor is reported.