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2017, Number 3

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Revista Habanera de Ciencias Médicas 2017; 16 (3)

Identification in silico of potentially inhibitive molecules of CDK5, protein related with the Alzheimer´s disease

Pájaro-Castro N, Bustamante-Díaz J, Ibáñez-Bersinger C

Language: Spanish
References: 23
Page: 326-336
PDF size: 656.74 Kb.


ABSTRACT

Introduction: The illness of Alzheimer exhibits a neurodegenerative and irreversible commitment. Today, numerous investigations promote the inhibition of some kinases to the treatment, of special mention the CDK5. Objective: Identification of new molecules witch are able to interact with the cicline dependent kinase protein 5, CDK5, inhibiting their function. Material and Methods: it was carried out a study in silico, for that 911 pubchem molecules were extracted, and by means of AutoDock Vina molecular joining, were made with the protein CDK5 extracted from the Protein Data Bank and with a well-known inhibitor for the protein. It was also carried out an inverse joining for the identification of other possible molecular targets with the best-selected ligands. Results: With the obtained results five molecules were identified with values of likeness among -11,6 until -17,7 Kcal/mol that joins in the active site of the protein, in the same form that makes it the well-known inhibitor of the CDK5, and interact with the residuals cysteine 83 and glutamine 81. Conclusions: The identified molecules can interact with the CDK5 at level of their active place, for what you/they could act as inhibitors of this quinasa. This opens a future therapeutic window in the treatment of the illness of Alzheimer.


REFERENCES

  1. Reitz C, Mayeux R. Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol [Internet]. 2014 Consultado: 2016 Ago 02; 88: 640–651. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/24398425

  2. Bernhardi R. Neurobiological mechanisms of Alzheimer's disease. Rev Chil Neuro-Psiquiatr [Internet]. 2005 Consultado: 2016 Ago 02]. 43(2):123-132Disponible en: http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0717-92272005000200005

  3. Zamolodchikov D, Strickland S. A possible new role for Aβ in vascular and inflammatory dysfunction in Alzheimer's disease. Thromb Res [Internet]. 2016 May Consultado: 2016 Ago 04; 141(2):59–61Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/27207427

  4. López O. Tratamiento farmacológico de la enfermedad de Alzheimer y otras demencias. Arch Med Interna [Internet].2015 Consultado: 2016 Ago 06; 37(1):61-67. Disponible en: http://www.scielo.edu.uy/scielo.php?script=sci_arttext&pid=S1688-423X2015000200003

  5. Sharma HS, Muresanu DF, Sharma A. Alzheimer's disease: cerebrolysin and nanotechnology as a therapeutic strategy. Neurodegener Dis Manag [Internet]. 2016 Dic Consultado: 2016 Ago 10; 6(6):453-456. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/27827552

  6. Herrera M, Hernández M, Manzo J, Aranda G. Enfermedad de Alzheimer: inmunidad y diagnóstico. Rev Neurol [Internet]. 2010 Consultado: 2016 Ago 15; 51(3): 153-164 Disponible en: http://www.neurologia.com/pdf/Web/5103/be030153.pdf

  7. Maccioni C, Arzola M, Mujica L, Maccion R. Nuevos paradigmas en el estudio de la patogénesis de la enfermedad de Alzheimer. Rev. chil. neuro-psiquiatr [Internet]. 2003 Consultado: 2017 Abr 15; 41(supl 2):33-46.]. Disponible en: http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0717-92272003041200005&lng=es&nrm=iso&tlng=es

  8. Williams P, Sorribas A, Howes MJ. Natural products as a source of Alzheimer's drug leads. Nat Prod Rep [Internet]. 2011 Consultado: 2017 Abr 15; 28(1):48-77. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/21072430

  9. Li H, Zheng M, Luo X, Zhu W, Jiang H. Computational approaches in drug discovery and development. Wiley encyclopedia of chemical biology [Internet]. 2008 Consultado: 2017 Abr 15]. Disponible en: http://onlinelibrary.wiley.com/doi/10.1002/9780470048672.wecb098/abstract;jsessionid=F09909716C68BF68B8AE25FC83E1BD3D.f01t01?systemMessage=Pay+Per+View+on+Wiley+Online+Library+will+be+unavailable+on+Saturday+15th+April+from+12%3A00-09%3A00+EDT+for+essential+maintenance.++Apologies+for+the+inconvenience.&userIsAuthenticated=false&deniedAccessCustomisedMessage=

  10. Pierri C, Parisi G, Porcelli V. Computational approaches for protein function prediction: A combined strategy from multiple sequence alignment to molecular docking-based virtual screening. Biochim Biophys Acta [Internet]. 2010 Consultado: 2017 Abr 15; 1804(9):1695-712. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/20433957

  11. Pájaro N, Flechas M, Ocazionez R, Stashenko E, Olivero J. Potential interaction of components from essential oils with dengue virus proteins. Bol Latin Carib Plant Medic Aromát [Internet]. 2015 Consultado: 2016 Sep 03; 14(3):141–155. Disponible en: http://www.redalyc.org/articulo.oa?id=85638535001

  12. Ahn JS, Radhakrishnan ML, Mapelli M, Choi S, Tidor B, Cuny GD, et al.Defining Cdk5 ligand chemical space with small molecule inhibitors of Tau phosphorylation. Chem Biol [Internet]. 2005 Consultado: 2016 Sep 18; 12:811–23. Disponible en: http://www.cell.com/ccbio/abstract/S1074-5521(05)00157-2

  13. Gao-keng X, Hao G, Xin-sheng Y. Alzheimer´s Disease target prediction Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China. [Internet]. Consultado: 2016 Nov 05]. Disponible en: http://nps.jnu.edu.cn

  14. Demange L, Abdellah FN, Lozach O, Ferandin Y, Gresh N, Meijer L, et al. Potent inhibitors of CDK5 derived from roscovitine: Synthesis, biological evaluation and molecular modelling. Bioorg Med Chem Lett [Internet]. 2013 Consultado: 2016 Oct 15; 23:125–31. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/23218601

  15. Chatterjee A, Cutler SJ, Doerksen RJ, Khan IA, Williamson JS. Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening. Bioorg Med Chem [Internet]. 2014 Consultado: 2016 Oct 22; 22(22) :6409-21 Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/?term=Discovery+of+thienoquinolone+derivatives+as+selective+and+ATP+non-competitive+CDK5%2Fp25+inhibitors+by+structure-based+virtual+screening

  16. Dong K, Wang X, Yang X, Zhu X. Binding mechanism of CDK5 with roscovitine derivatives based on molecular dynamicssimulations and MM/PBSA methods. J Mol Graph Model [Internet]. 2016 Consultado: 2016 Nov 02;68:57-67. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/?term=Binding+Mechanism+of+CDK5+with+Roscovitine+Derivatives+Based+on+Molecular+Dynamics+Simulations+and+MM%2FPBSA+Methods

  17. Shrestha S, Natarajan S, Park JH, Lee DY, Cho JG, Kim GS, et al. Potential neuroprotective flavonoid-based inhibitors of CDK5/p25 from Rhus parviflora. Bioorg Med Chem Lett.[Internet]. 2013Consultado: 2016 Nov 11;23(18):5150-54 Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/?term=Potential+neuroprotective+flavonoid-based+inhibitors+of+CDK5%2Fp25+from+Rhus+parviflora

  18. Mascayano C, Carolina L. Síntesis de derivados de 1-bencilisoquinolinas como posibles inhibidores de CDK5 y estudio de las interacciones en el sitio de unión de ATP. Universidad de Santiago de Chile, Facultad de Química y Biología. [Internet]. 2006 Consultado: 2016 Nov 11. Disponible en: http://dspace2.conicyt.cl/handle/10533/15016

  19. Nishikawa T, Takahashi T, Nakamori M, Yamazaki Y, Kurashige T, Nagano Y, et al. Phosphatidylinositol-4,5-bisphosphate is enriched in granulovacuolar degeneration bodies and neurofibrillary tangles. Neuropathol Appl Neurobiol [Internet]. 2014 Jun Consultado: 2016 Nov 24; 40(4):489-501. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/?term=Phosphatidylinositol-4%2C5-bisphosphate+is+enriched+in+granulovacuolar+degeneration+bodies+and+neurofibrillary+tangles.

  20. Haddad J. Mitogen-activated protein kinases and the evolution of Alzheimer's: a revolutionary neurogenetic axis for therapeutic intervention? Prog Neurobiol [Internet]. 2004 Ago Consultado: 2016 Nov 28;73(5):359-77. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/?term=Mitogen-activated+protein+kinases+and+the+evolution+of+Alzheimer%E2%80%99s%3A+a+revolutionary+neurogenetic+axis+for+therapeutic+intervention%3F%2C

  21. Alam J, Scheper W. Targeting neuronal MAPK14/p38αactivity to modulate autophagy in the Alzheimer disease brain. Autophagy [Internet]. 2016 Dic Consultado: 2016 Dic 03; 12(12):2516-20]. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/?term=Targeting+neuronal+MAPK14%2Fp38%CE%B1+activity+to+modulate+autophagy+in+the+Alzheimer+disease+brain

  22. Bales K, Plath N, Svenstrup N, Menniti F. Phosphodiesterase inhibition to target the synaptic dysfunction in Alzheimer’s disease. Top Med Chem [Internet]. 2010 Ago Consultado: 2016 Dic 10; 6:57–90. . Disponible en: http://link.springer.com/chapter/10.1007%2F7355_2010_8

  23. Rodríguez C, Rimola A, Alí J, González P, Sodupe M. Estrategias in silico para el diseño y selección de compuestos con potencial aplicación en la enfermedad de Alzheimer. FarmaEspaña Ind [Internet]. 2011 Nov-Dec Consultado: 2017 Abr 15; 1:66-8. Disponible en http://www.xrqtc.com/wp-content/uploads/2014/07/alzheimer.pdf




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