MOLECULAR DOCKING STUDY ON 1H-(3,4d) PYRAZOLO-PYRIMIDINES AS CYCLIN DEPENDANT KINASE (CDK2) INHIBITORS
Objective: CDK2 inhibitors are implicated in several carcinomas viz. Carcinoma of lung, bladder, sarcomas and retinoblastoma. Pyrazolopyrimidines, being purine bioisosters inhibit more than one type of kinase. In this study, we are studying some novel derivatives of 1H-pyrazolo [3,4d] pyrimidines not reported earlier. The objective of the present study is an attempt towards design and development of 1H-[3,4-] pyrazolo-pyrimidines as CDK2 inhibitors through rational drug design.
Methods: The present study has been done on CDK2 structure, PDB ID, 3WBL, co-crystallized with ligand PDY from RCSB protein data bank. A series of seventeen 1H-Pyrazolo [3,4-d] pyrimidines feasible for synthesis was docked on the said CDK2 receptor using Auto Dock 4 version, 1.5.6. Outputs were exported to discovery studio 3.5 client for visual inspection of the binding modes and interactions of the compounds with amino acid residues in the active sites.
Results: The results of docking studies revealed that the present series of 1H-Pyrazolo[3,4-d] pyrimidines is showing significant binding through hydrogen bonding, hydrophobic, pi and Van der waals interactions, similar to the ligand PDY. Some conserved H-bond interactions comparable to bioisosters and compounds presently under human trials were noted. Ki values predicted in silico also suggest that the series will show promising CDK2 inhibitory activity.
Conclusion: The series designed and docked can be further developed by synthesis and in vitro and in vivo activity. The receptor inhibitory activity can also be checked by specific receptor assays.
2. McConnell JL, Wadzinski BE. Targeting protein serine/ threonine phosphatases for drug development. Mol Pharmacol 2009;75:1249â€“61.
3. Taylor SS, Kornev AP. Protein kinases: evolution of dynamic regulatory proteins. Trends Biochem Sci 2011;36:65â€“77.
4. Fischer PM. The use of CDK 2 inhibitors in cancer. Cell Cycle 2004;3:742-6.
5. Kim DC, Lee YR, Yang BS, Shin KJ, Kim DJ, Chung BY, et al. Synthesis and biological evaluations of pyrazolo [3,4-d]pyrimidines as cyclin-dependent kinase 2 inhibitors. Eur J Med Chem 2003;38:525-32.
6. 5a. Balajee R, Dhana Rajan MS. Comparative study of inhibition of drug potencies of tyrosine kinase inhibitors: a computational and molecular docking study. Asian J Pharm Clin Res 2012;1:104-8.
7. Shchemelinin I, Å efc L, NeÄas E. Protein kinases, their function and implication in cancer and other diseases. Folia Biol (Praha) 2006;52:81-101.
8. Mariaule G, Belmont P. Cyclin-dependent kinase inhibitors as marketed anticancer drugs: where are we now? a short survey. Molecules 2014;19:14366-82.
9. Balakrishnan A, Vyas A, Deshpande K, Vyas D. Pharmacological cyclin-dependent kinase inhibitors: implications for colorectal cancer. World J Gastroenterol 2016;21(22 Suppl 7):2159-64.
10. Ghorab MM, Ragab FA, Alqasoumi SI, Alafeefy AM, Aboulmagd SA. Synthesis of some new pyrazolo [3,4-d]pyrimidine derivatives of expected anticancer and radioprotective activity. Eur J Med Chem 2010;45:171â€“8.
11. Rashad AE, Mahmoud AE, Ali MM. Synthesis and anticancer effects of some novel pyrazolo [3,4-d]pyrimidine derivatives by generating reactive oxygen species in human breast adenocarcinoma cells. Eur J Med Chem 201;4:1019-26.
12. El-Enany MM, Kamel MM, Khalil OM, El-Nassan HB. Synthesis and antitumor activity of novel 6-aryl and 6-alkylpyrazolo[3,4-d]pyrimidin-4-one derivatives. Eur J Med Chem 2010;45:5286-91.
13. Kumar A, Ahmad I, Chhikara BS, Tiwari R, Mandal D, Parang K. Synthesis of 3-phenyl pyrazolopyrimidine-1,2,3-triazole conjugates and evaluation of their Src kinase inhibitory and anticancer activities. Bioorg Med Chem Lett 2011;21:1342-6.
14. Hassan GS, Kadry HH, Abou-Seri SM, Ali MM, Mahmoud AE. Synthesis and in vitro cytotoxic activity of novel pyrazolo[3,4-d]pyrimidines and related pyrazole hydrazones towards breast adenocarcinoma MCF-7 cell line. Bioorg Med Chem 2011;19:6808-17.
15. Pal D, Saha S, Singh A. Importance of pyrazole moeity in the field of cancer. Int J Pharm Pharn Sci 2012;4:98-104.
16. Kim DC, Lee YR, Yang B, Shin KJ, Kim DJ, Chung BY, et al. Synthesis and biological evaluations of pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 inhibitors. Eur J Med Chem 2003;38:525-32.
17. Markwalder JA, Arnone MR, Benfield PA, Boisclair M, Burton CR, Chang C, et al. Synthesis and biological evaluation of 1-Aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of cyclin dependent kinases. J Med Chem 2004;47:5894-911.
18. Peat AJ, Boucheron JA, Dickerson SH, Garrido D, Mills W, Peckham J, et al. Novel pyrazolopyrimidine derivatives as GSK-3 inhibitors. Bioorg Med Chem Lett 2004;14:2121-5.
19. Schenone S, Bruno O, Bondavalli F, Ranise A, Mosti L, Menozzi G. Antiproliferative activity of new 1-aryl-4-amino-1H-pyrazolo[3,4-d]pyrimidine derivatives toward the human epidermoid carcinoma A431 cell line. Eur J Med Chem 2004;39:939-46.
20. Ducray R, Ballard P, Barlaam BC, Hickinson MD, Kettle JG, Ogilvieb DJ, et al. Novel 3-alkoxy-1H-pyrazolo[3,4-d]pyrimidines as EGFR and erbB2 receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett 2008;18:959-62.
21. Schenone S, Bruno O, Bondavalli F, Ranise A, Mosti L, Menozzi G, et al. Synthesis of 1-(2-chloro-2-phenylethyl)-6-methylthio-1H-pyrazolo[3,4-d]pyrimidines 4-amino substituted and their biological evaluation. Eur J Med Chem 2004;39:153â€“60.
22. Curran KJ, Verheijen JC, Kaplan J, Richard DJ, Toral-Barza L, Hollander I. pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimisation of the 1-substituent. Bioorg Med Chem Lett 2010;20:1440-4.
23. Schenone S, Brullo C, Bruno O, Bondavalli F, Mosti L, Maga G, et al. Synthesis, biological evaluation and docking studies of 4-amino substituted 1H-pyrazolo[3,4-d]pyrimidines. Eur J Med Chem 2008;43:2665-76.
24. Peat AJ, Garrido D, Boucheron JA, Schweiker SL, Dickerson SH, Wilson JR, et al. Novel GSK-3 inhibitors with improved cellular activity. Bioorg Med Chem Lett 2004;14:2127-30.
25. Smalley TL, Peat AJ, Boucheron JA, Dickerson S, Garrido D, Preugschat F. Synthesis and evaluation of novel heterocyclic inhibitors of GSK-3. Bioorg Med Chem Lett 2006;16:2091-4.
26. Luma C, Kahl J, Kessler L, Kucharski J, Lundstrm J, Miller S. 2,5-Diaminopyrimidines and 3,5-disubstituted aza purines as inhibitors of glycogen synthase kinase-3 (GSK-3). Bioorg Med Chem Lett 2008;18:3578-81.
27. Rashad AE, Mahmoudb AE, Ali MM. Synthesis and anticancer effects of some novel pyrazolo[3,4-d]pyrimidine derivatives by generating reactive oxygen species in human breast adenocarcinoma cells. Eur J Med Chem 2011;46:1019-26.
28. Popowycz F, Fournet G, Schneider C, Bettayeb K, Ferandin Y, Lamigeon C, et al. Pyrazolo[1,5-a]-1,3,5-triazine as a purine bioisostere: access to potent cyclin-dependent kinase inhibitor (R)-roscovitine analogue. J Med Chem 2009;52:655-63.
29. Abdulilah E, Sevin F. The discovery of potential cyclin A/CDK2 inhibitors: a combination of 3D QSAR pharmacophore modeling, virtual screening, and molecular docking studies. Med Chem Res 2013;22:5832-43.
30. Biswal S, Sahoo U, Sethy S, Kumar HKS, Banerjee M. Indole: the molecule of diverse biological activities. Asian J Pharm Clin Res 2012;5:1-6.
31. Thomas N, Zachariah SM. Pharmacological activities of chromene derivatives: an overview. Asian J Pharm Clin Res 2013;6:11-5.
32. Kavitha S, Gnanavel S, Kannan K. Biological aspects of 1,3,4-oxadiazole derivatives. Asian J Pharm Clin Res 2014;7:11-20.
33. Ray S, Charusmriti. A QSAR study at AM1 semi-empirical level of 1, 3-diaryl pyrazole derivatives as antitumor agents against human DU145 prostrate cancer cell line. Asian J Pharm Clin Res 2012;5:160-3.
34. Eatedal HA, Nermine AM, Amany MM, Alaa NH. Synthesis of new pyrimidine derivatives and evaluation of their anticancer and antimicrobial activities. Asian J Pharm Clin Res 2016;9:306-13.
35. Guttikonda V, Raavi D, Maadwar SK, Gade RD. Molecular insights of benzopyrazole as CDK2 inhibitors: combined molecular docking, molecular dynamics, and 3D QSAR studies. J Recept Signal Transduct Res 2015;35:439-49.
36. Chandra, Javaregowda VG, Doreswamy BH, Ningaiah S, Bhadraiah UK, Kemparaju K, et al. Molecular docking studies of 1H pyrazole to receptor tyrosine kinase and protein kinase for screening potential inhibitors. Bioinformation 2014;10:413-8.
37. Vadivelan S, Sinha BN, Irudayam SJ, Sarma Jagarlapudi ARP. Virtual screening studies to design potent CDK2-cyclin inhibitors. J Chem Inf Model 2007;47:1526-35.
38. N-(Cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-Dependent kinase 2. N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methylthio]-2-thiazolyl]-4-piperidine-carboxamide (BMS-387032), a highly efficacious and selective antitumour agent. J Med Chem 2004;47:1719-28.