Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines
Language English Country France Media print-electronic
Document type Journal Article
PubMed
28039837
DOI
10.1016/j.ejmech.2016.12.023
PII: S0223-5234(16)31029-7
Knihovny.cz E-resources
- Keywords
- ATP-competitive type I inhibitors, Cyclin-dependent kinase 2, Molecular dynamics, Protein-ligand binding, Pyrazolo[1,5-a]pyrimidine, Quantum mechanical scoring, Water thermodynamics, X-ray crystal structure,
- MeSH
- Cyclin A metabolism MeSH
- Cyclin-Dependent Kinase 2 antagonists & inhibitors chemistry metabolism MeSH
- Protein Kinase Inhibitors chemistry metabolism pharmacology MeSH
- Catalytic Domain * MeSH
- Quantum Theory * MeSH
- Humans MeSH
- Pyrimidines chemistry metabolism pharmacology MeSH
- Drug Design MeSH
- Solvents chemistry MeSH
- Molecular Dynamics Simulation MeSH
- Water chemistry MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Cyclin A MeSH
- Cyclin-Dependent Kinase 2 MeSH
- Protein Kinase Inhibitors MeSH
- Pyrimidines MeSH
- Solvents MeSH
- Water MeSH
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.
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