Skip to main content

Advertisement

SpringerLink
Log in

Computational study of the inhibitory mechanism of the kinase CDK5 hyperactivity by peptide p5 and derivation of a pharmacophore

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

The hyperactivity of the cyclic dependent kinase 5 (CDK5) induced by the activator protein p25 has been linked to a number of pathologies of the brain. The CDK5–p25 complex has thus emerged as a major therapeutic target for Alzheimer’s disease (AD) and other neurodegenerative conditions. Experiments have shown that the peptide p5 reduces the CDK5–p25 activity without affecting the endogenous CDK5–p35 activity, whereas the peptide TFP5, obtained from p5, elicits similar inhibition, crosses the blood–brain barrier, and exhibits behavioral rescue of AD mice models with no toxic side effects. The molecular basis of the kinase inhibition is not currently known, and is here investigated by computer simulations. It is shown that p5 binds the kinase at the same CDK5/p25 and CDK5/p35 interfaces, and is thus a non-selective competitor of both activators, in agreement with available experimental data in vitro. Binding of p5 is enthalpically driven with an affinity estimated in the low µM range. A quantitative description of the binding site and pharmacophore is presented, and options are discussed to increase the binding affinity and selectivity in the design of drug-like compounds against AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Nikolic M, Dudek H, Kwon YT, Ramos YF, Tsai LH (1996) The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev 10:816–825

    Article  CAS  Google Scholar 

  2. Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna Pant HC et al (1996) Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci USA 93:11173–11178

    Article  CAS  Google Scholar 

  3. Tan TC, Valova VA, Malladi CS, Graham ME, Berven LA, Jupp OJ et al (2003) Cdk5 is essential for synaptic vesicle endocytosis. Nat Cell Biol 5:701–710

    Article  CAS  Google Scholar 

  4. Ahlijanian MK, Barrezueta NX, Williams RD, Jakowski A, Kowsz KP, McCarthy S et al (2000) Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5. Proc Natl Acad Sci USA 97:2910–2915

    Article  CAS  Google Scholar 

  5. de la Monte SM, Ganju N, Feroz N, Luong T, Banerjee K, Cannon J et al (2000) Oxygen free radical injury is sufficient to cause some Alzheimer type molecular abnormalities in human CNS neuronal cells. J Alzheimer’s Dis 2:261–281

    Google Scholar 

  6. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (1999) Conversion of p35 to p25 deregulates CDK5 activity and promotes neurodegeneration. Nature 402:615–622

    Article  CAS  Google Scholar 

  7. Shukla V, Zheng YL, Mishra SK, Amin ND, Steiner J, Grant P et al (2013) A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer’s disease phenotypes in model mice. FASEB J 27:174–186

    Article  CAS  Google Scholar 

  8. Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405:360

    Article  CAS  Google Scholar 

  9. Noble W, Olm V, Takata K, Casey E, Mary O, Meyerson J et al (2003) CDK5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38:555–565

    Article  CAS  Google Scholar 

  10. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H et al (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6:916–919

    Article  CAS  Google Scholar 

  11. Maier M, Seabrook TJ, Lazo ND, Jiang L, Das P, Janus C et al (2006) Short amyloid-beta (Abeta) immunogens reduce cerebral Abeta load and learning deficits in an Alzheimer’s disease mouse model in the absence of an Abeta-specific cellular immune response. J Neurosci 26:4717–4728

    Article  CAS  Google Scholar 

  12. Ritchie CW, Ames D, Clayton T, Lai R (2004) Meta-analysis of randomized trials of the efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer disease. Am J Geriatr Psychiatry 12:358–369

    Article  Google Scholar 

  13. Bonda DJ, Wang X, Perry G, Nunomura A, Tabaton M, Zhu X et al (2010) Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology 59:290–294

    Article  CAS  Google Scholar 

  14. Lee HP, Zhu X, Casadesus G, Castellani RJ, Nunomura AS, Smith MA, Lee HG et al (2010) Antioxidant approaches for the treatment of Alzheimer’s disease. Expert Rev Neurother 10:1201–1208

    Article  Google Scholar 

  15. Helal CJ, Sanner MA, Cooper CB, Gant T, Adam M, Lucas JC et al (2004) Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer’s disease. Bioorg Med Chem Lett 14:5521–5525

    Article  CAS  Google Scholar 

  16. Helal CJ, Kang Z, Lucas JC, Gant T, Ahlijanian MK, Schachter JB et al (2009) Potent and cellularly active 4 aminoimidazole inhibitors of cyclin-dependent kinase 5/p25 for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 19:5703–5707

    Article  CAS  Google Scholar 

  17. Knockaert M, Wieking K, Schmitt S, Leost M, Grant KM, Mottram JC et al (2002) Intracellular targets of paullones. Identification following affinity purification on immobilized inhibitor. J Biol Chem 277:25493–25501

    Article  CAS  Google Scholar 

  18. Zheng YL, Kesavapany S, Gravell M, Hamilton RS, Schubert M, Amin ND et al (2005) A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons. EMBO J 24:209–220

    Article  CAS  Google Scholar 

  19. Zheng YL, Amin ND, Hu YF, Rudrabhatla P, Shukla VK, Kanungo J et al (2010) A 24-residue peptide (p5), derived from p35, the cdk5 neuronal activator, specifically inhibits CDK5–p25 hyperactivity and tau hyperphosphorylation. J Biol Chem 285:34202–34212

    Article  CAS  Google Scholar 

  20. Binukumar BK, Zheng YL, Shukla V, Amin ND, Grant P, Pant HC (2014) TFP5, a peptide derived from p35, a CDK5 neuronal activator, rescues cortical neurons from glucose toxicity. J Alzheimer’s Dis 39:899–909

    CAS  Google Scholar 

  21. Cardone A, Pant H, Hassan SA (2013) Specific and non-specific protein association in solution: computation of solvent effects and prediction of first-encounter modes for efficient configurational bias Monte Carlo simulations. J Phys Chem B 117:12360–12374

    Article  CAS  Google Scholar 

  22. Cardone A, Bornstein A, Pant HC, Brady M, Sriram R, Hassan SA (2015) Detection and characterization of nonspecific, sparsely-populated binding modes in the early stages of complexation. J Comput Chem 36:983–995

    Article  CAS  Google Scholar 

  23. Hassan SA, Steinbach PJ (2011) Water-exclusion and liquid-structure forces in implicit solvation. J Phys Chem B. 115:14668

    Article  CAS  Google Scholar 

  24. Hassan SA, Mehler EL (2012) In silico approaches to structure and function of cell components and their assemblies: molecular electrostatics and solvent effects. In: Egelman E (ed) Comprehensive biophysics. Academic Press, New York

    Google Scholar 

  25. Hassan SA (2014) Implicit treatment of solvent dispersion forces in protein simulations. J Comput Chem 35:1621–1629

    Article  CAS  Google Scholar 

  26. Tang C, Ghirlando R, Clore GM (2008) Visualization of transient ultra-weak protein self-association in solution using paramagnetic relaxation enhancement. J Am Chem Soc 130:4048

    Article  CAS  Google Scholar 

  27. Johansson H, Jensen MR, Gesmar H, Meier S, Vinther JM, Keeler C et al (2014) Specific and nonspecific interactions in ultraweak protein-protein association revealed by solvent paramagnetic relaxation enhancements. J Am Chem Soc 136:10277–10286

    Article  CAS  Google Scholar 

  28. Tarricone C, Dhavan R, Peng J, Areces LB, Tsai LH, Musacchio A (2001) Structure and regulation of the CDK5–p25(nck5a) complex. Mol Cell 8:657

    Article  CAS  Google Scholar 

  29. Steinbach PJ (2004) Exploring peptide energy lanscapes:a test of force fields and implicit solvent models. Proteins 57:665

    Article  CAS  Google Scholar 

  30. Brooks BR, Brooks CL, Mackerell AD, Nilsson L, Petrella RJ, Roux B et al (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30:1545

    Article  CAS  Google Scholar 

  31. Hassan SA, Mehler EL, Zhang D, Weinstein H (2003) Molecular dynamics simulations of peptides and proteins with a continuum electrostatic model based on screened Coulomb potentials. Proteins 51:109–125

    Article  CAS  Google Scholar 

  32. Hassan SA, Mehler EL (2005) From quantum chemistry and the classical theory of polar liquids to continuum approximations in molecular mechanics calculations. Int J Quantum Chem 102:986

    Article  CAS  Google Scholar 

  33. Szekely GJ, Rizzo ML (2005) Hierarchical clustering via joint between-within distances: extending Ward’s minimum variance method. J Classif 22:151–183

    Article  Google Scholar 

  34. Mapelli M, Massimiliano L, Crovace C, Seeliger MA, Tsai LH, Meijer L et al (2005) Mechanism of CDK5/p25 binding by CDK inhibitors. J Med Chem 48:671

    Article  CAS  Google Scholar 

  35. Cardone A, Hassan SA, Albers RW, Sriram RD, Pant HC (2010) Structural and dynamic determinants of ligand binding and regulation of cyclin-dependent kinase 5 by pathological activator p25 and inhibitory peptide CIP. J Mol Biol 401:478–492

    Article  CAS  Google Scholar 

  36. Cardone A, Albers RW, Sriram RD, Pant HC (2010) Evaluation of the interaction of cyclin-dependent kinase 5 with activator p25 and with p25-derived inhibitor CIP. J Comput Biol 17:1–15

    Article  Google Scholar 

  37. D’Aquino JA, Freire E, Amzel LM (2000) Binding of small organic molecules to macromolecular targets: evaluation of conformational entropy changes. Proteins Struct Funct Genet 41(S4): 93–107

    Article  Google Scholar 

  38. Yu YB, Privalov PL, Hodges RS (2001) Contribution of translational and rotational motions to molecular association in aqueous solution. Biophys J 81:1632–1642

    Article  CAS  Google Scholar 

  39. Andricioaei I, Karplus M (2001) On the calculation of entropy from covariance matrices of the atomic fluctuations. J Chem Phys 115:6289–6292

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study utilized the high-performance computer capabilities of the Biowulf PC/Linux cluster at the NIH. This work was supported by the NIH Intramural Research Program through the CIT and NINDS, and an internal NIST Research Fund.

Author information

Authors and Affiliations

  1. Software and System Division, National Institute of Standards and Technology, Gaithersburg, MD, 20899, USA

    A. Cardone, M. Brady & R. Sriram

  2. Institute for Advanced Computer Studies, University of Maryland, College Park, MD, 20742, USA

    A. Cardone

  3. Laboratory of Neurochemistry, NINDS, National Institutes of Health, Bethesda, MD, 20892, USA

    H. C. Pant

  4. Center for Molecular Modeling, Division of Computational Bioscience, CIT, National Institutes of Health, Bethesda, MD, 20892, USA

    S. A. Hassan

Authors
  1. A. Cardone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Brady
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Sriram
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. C. Pant
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. A. Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Cardone.

Additional information

Disclaimer Commercial products are identified in this document in order to specify the experimental procedure adequately. Such identification is not intended to imply recommendation or endorsement by the National Institute of Standards and Technology or the National Institutes of Health, nor is it intended to imply that the products identified are necessarily the best available for the purpose.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cardone, A., Brady, M., Sriram, R. et al. Computational study of the inhibitory mechanism of the kinase CDK5 hyperactivity by peptide p5 and derivation of a pharmacophore. J Comput Aided Mol Des 30, 513–521 (2016). https://doi.org/10.1007/s10822-016-9922-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-016-9922-3

Keywords

Search

Navigation