5LMK

Structure of phopsho-CDK2-cyclin A in complex with an ATP-competitive inhibitor

Summary for 5LMK

• Entry DOI: 10.2210/pdb5lmk/pdb
• Descriptor: Cyclin-dependent kinase 2, Cyclin-A2, 4-[4-[3-bromanyl-7-(pyridin-3-ylmethylamino)pyrazolo[1,5-a]pyrimidin-5-yl]phenyl]benzamide, ... (7 entities in total)
• Functional Keywords: cdk2; cyclin a, cell cycle, transferase, inhibitor, complex
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 128504.68

Authors

Echalier, A. (deposition date: 2016-08-01, release date: 2017-01-25, Last modification date: 2024-10-16)

Primary citation

Hylsova, M.,Carbain, B.,Fanfrlik, J.,Musilova, L.,Haldar, S.,Kopruluoglu, C.,Ajani, H.,Brahmkshatriya, P.S.,Jorda, R.,Krystof, V.,Hobza, P.,Echalier, A.,Paruch, K.,Lepsik, M.
Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines.
Eur J Med Chem, 126:1118-1128, 2016

PubMed Abstract: 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 = 0.49). However, the addition of the active-site waters resulted in significant improvement (R = 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.

PubMed: 28039837
DOI: 10.1016/j.ejmech.2016.12.023

Experimental method

X-RAY DIFFRACTION (2.4 Å)