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Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design.

Kontopidis G, McInnes C, Pandalaneni SR, McNae I, Gibson D, Mezna M, Thomas M, Wood G, Wang S, Walkinshaw MD, Fischer PM
Chem Biol 13 201-11 (2006)
Related entries: 2c5n, 2c5v, 2c5x, 2c5y

Cited: 25 times
EuropePMC logo PMID: 16492568

Abstract

The cyclin-dependent kinases (CDKs) have been characterized in complex with a variety of inhibitors, but the majority of structures solved are in the inactive form. We have solved the structures of six inhibitors in both the monomeric CDK2 and binary CDK2/cyclinA complexes and demonstrate that significant differences in ligand binding occur depending on the activation state. The binding mode of two ligands in particular varies substantially in active and inactive CDK2. Furthermore, energetic analysis of CDK2/cyclin/inhibitors demonstrates that a good correlation exists between the in vitro potency and the calculated energies of interaction, but no such relationship exists for CDK2/inhibitor structures. These results confirm that monomeric CDK2 ligand complexes do not fully reflect active conformations, revealing significant implications for inhibitor design while also suggesting that the monomeric CDK2 conformation can be selectively inhibited.

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Reviews citing this publication (1)

  1. Ligand discovery and virtual screening using the program LIDAEUS. Taylor P, Blackburn E, Sheng YG, Harding S, Hsin KY, Kan D, Shave S, Walkinshaw MD. Br J Pharmacol 153 Suppl 1 S55-67 (2008)

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  1. On the relation between residue flexibility and local solvent accessibility in proteins. Zhang H, Zhang T, Chen K, Shen S, Ruan J, Kurgan L. Proteins 76 617-636 (2009)
  2. Redefining the Protein Kinase Conformational Space with Machine Learning. Ung PM, Rahman R, Schlessinger A. Cell Chem Biol 25 916-924.e2 (2018)
  3. A kinetic test characterizes kinase intramolecular and intermolecular autophosphorylation mechanisms. Dodson CA, Yeoh S, Haq T, Bayliss R. Sci Signal 6 ra54 (2013)
  4. Reduced stability and increased dynamics in the human proliferating cell nuclear antigen (PCNA) relative to the yeast homolog. De Biasio A, Sánchez R, Prieto J, Villate M, Campos-Olivas R, Blanco FJ. PLoS One 6 e16600 (2011)
  5. NEK1 kinase domain structure and its dynamic protein interactome after exposure to Cisplatin. Melo-Hanchuk TD, Slepicka PF, Meirelles GV, Basei FL, Lovato DV, Granato DC, Pauletti BA, Domingues RR, Leme AFP, Pelegrini AL, Lenz G, Knapp S, Elkins JM, Kobarg J. Sci Rep 7 5445 (2017)
  6. PDB-Explorer: a web-based interactive map of the protein data bank in shape space. Jin X, Awale M, Zasso M, Kostro D, Patiny L, Reymond JL. BMC Bioinformatics 16 339 (2015)
  7. Structural features underlying selective inhibition of GSK3β by dibromocantharelline: implications for rational drug design. Zhang N, Zhong R, Yan H, Jiang Y. Chem Biol Drug Des 77 199-205 (2011)
  8. Truncation and optimisation of peptide inhibitors of cyclin-dependent kinase 2-cyclin a through structure-guided design. Kontopidis G, Andrews MJ, McInnes C, Plater A, Innes L, Renachowski S, Cowan A, Fischer PM. ChemMedChem 4 1120-1128 (2009)
  9. Development of a novel fluorescent probe for fluorescence correlation spectroscopic detection of kinase inhibitors. Kawaguchi M, Terai T, Utata R, Kato M, Tsuganezawa K, Tanaka A, Kojima H, Okabe T, Nagano T. Bioorg Med Chem Lett 18 3752-3755 (2008)
  10. Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines. Hylsová M, Carbain B, Fanfrlík J, Musilová L, Haldar S, Köprülüoğlu C, Ajani H, Ajani H, Brahmkshatriya PS, Jorda R, Kryštof V, Hobza P, Echalier A, Paruch K, Lepšík M. Eur J Med Chem 126 1118-1128 (2017)
  11. Evaluation of protein-ligand affinity prediction using steered molecular dynamics simulations. Okimoto N, Suenaga A, Taiji M. J Biomol Struct Dyn 35 3221-3231 (2017)
  12. Catch the kinase conformer. McInnes C, Mezna M, Kontopidis G. Chem Biol 13 693-694 (2006)
  13. Discovery of New Pyrazolopyridine, Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design, Synthesis, Docking Studies, and Anti-Proliferative Activity. Abdel-Rahman AA, Shaban AKF, Nassar IF, El-Kady DS, Ismail NSM, Mahmoud SF, Awad HM, El-Sayed WA. Molecules 26 3923 (2021)
  14. Evaluating the enthalpic contribution to ligand binding using QM calculations: effect of methodology on geometries and interaction energies. Gleeson D, Tehan B, Gleeson MP, Limtrakul J. Org Biomol Chem 10 7053-7061 (2012)
  15. Polyphony: superposition independent methods for ensemble-based drug discovery. Pitt WR, Montalvão RW, Blundell TL. BMC Bioinformatics 15 324 (2014)
  16. Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles. Nekardová M, Vymětalová L, Khirsariya P, Kováčová S, Hylsová M, Jorda R, Kryštof V, Fanfrlík J, Hobza P, Paruch K. Chemphyschem 18 785-795 (2017)
  17. CDK Inhibition Primes for Anti-PD-L1 Treatment in Triple-Negative Breast Cancer Models. Cheung A, Chenoweth AM, Quist J, Sow HS, Malaktou C, Ferro R, Hoffmann RM, Osborn G, Sachouli E, French E, Marlow R, Lacy KE, Papa S, Grigoriadis A, Karagiannis SN. Cancers (Basel) 14 3361 (2022)
  18. Role of interactions and volume variation in discriminating active and inactive forms of cyclin-dependent kinase-2 inhibitor complexes. Saranya N, Selvaraj S. Chem Biol Drug Des 78 361-369 (2011)
  19. Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial PfGSK3/PfPK6 with Activity against Blood Stage Parasites In Vitro. Galal KA, Truong A, Kwarcinski F, de Silva C, Avalani K, Havener TM, Chirgwin ME, Merten E, Ong HW, Willis C, Abdelwaly A, Helal MA, Derbyshire ER, Zutshi R, Drewry DH. J Med Chem 65 13172-13197 (2022)
  20. Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity. Mandour AA, Nassar IF, Abdel Aal MT, Shahin MAE, El-Sayed WA, Hegazy M, Yehia AM, Ismail A, Hagras M, Elkaeed EB, Refaat HM, Ismail NSM. J Enzyme Inhib Med Chem 37 1957-1973 (2022)
  21. Conformation-dependent ligand hot spots in the spliceosomal RNA helicase BRR2. Vester K, Metz A, Huber S, Loll B, Wahl MC. Acta Crystallogr D Struct Biol 79 304-317 (2023)
  22. Discovery of pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives as novel CDK2 inhibitors: synthesis, biological and molecular modeling investigations. Nassar IF, Abdel Aal MT, El-Sayed WA, A E Shahin M, Elsakka EGE, Mokhtar MM, Hegazy M, Hagras M, Mandour AA, Ismail NSM. RSC Adv 12 14865-14882 (2022)
  23. Imidazo[1,2-c]pyrimidin-5(6H)-one as a novel core of cyclin-dependent kinase 2 inhibitors: Synthesis, activity measurement, docking, and quantum mechanical scoring. Ajani H, Jansa J, Köprülüoğlu C, Hobza P, Kryštof V, Lyčka A, Lepsik M. J Mol Recognit 31 e2720 (2018)


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