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Pyrazolo[3,4-d]pyrimidines as inhibitor of anti-coagulation and inflammation activities of phospholipase A 2 : insight from molecular docking studies

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Abstract

Phospholipase A2 (PLA2), isolated from Daboia russelli pulchella (Russell’s viper), is enzymatically active as well as induces several pharmacological disorders including neurotoxicity, myotoxicity, cardiotoxicity, anti-coagulant, hemolytic, and platelet effects. Indomethacin reduces the effects of anti-coagulant and pro-inflammatory actions of PLA2. Pyrazolo[3,4-d]pyrimidines constitute a class of naturally occurring fused uracils that posses diverse biological activities. The in-silico docking studies of nine pyrazolo[3,4-d]pyrimidine molecules have been carried out with the X-ray crystal structure of Russell’s viper PLA2 (PDB ID: 3H1X) to predict the binding affinity, molecular recognition, and to explicate the binding modes, using AUTODOCK and GLIDE (Standard precision and Extra precision) modules, respectively. Docking results through each method make obvious that pyrazolo[3,4-d]pyrimidine molecules with trimethylene linker can bind with both anti-coagulation and enzymatic regions of PLA2.

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References

  1. Grimme, S., Lichtenfeld, C.M., Antony, J.: Analysis of non-covalent interactions in (bio)organic molecules using orbital-partitioned localized MP2. Phys. Chem. Chem. Phys. 10, 3327–3334 (2008)

    Article  Google Scholar 

  2. Lee, E.C., Kim, D., Jurecka, P., Tarakeshwar, P., Hobza, P., Kim, K.S.: Understanding of assembly phenomena by aromatic-aromatic interactions: benzene dimer and the substituted systems. J. Phys. Chem. A 111, 3446–3457 (2007)

    Article  Google Scholar 

  3. Müller-Dethlefs, K., Hobza, P.: Noncovalent interactions: a challenge for experiment and theory. Chem. Rev. 100, 143–167 (2000)

    Article  Google Scholar 

  4. Sinnokrot, M.O., Sherrill, C.D.: High-accuracy quantum mechanical studies of π − π interactions in benzene dimers. J. Phys. Chem. A 110, 10656–10668 (2006)

    Article  Google Scholar 

  5. Cerny, J., Hobza, P.: The X3LYP extended density functional accurately describes H-bonding but fails completely for stacking. Phys. Chem. Chem. Phys. 7, 1624–1626 (2005)

    Article  Google Scholar 

  6. Tsuzuki, S., Honda, K., Uchimaru, K., Mikami, M., Tanabe, K.: Origin of attraction and directionality of the π/π interaction: model chemistry calculations of benzene dimer interaction. J. Am. Chem. Soc. 124, 104–112 (2002)

    Article  Google Scholar 

  7. Burley, S.K., Petsko, G.A.: Aromatic-aromatic interaction: a mechanism of protein structure stabilization. Science 229, 23–28 (1985)

    Article  ADS  Google Scholar 

  8. Tanaka, T., Tasaki, T., Aoyama, Y.: Acridinylresorcinol as a self-complementary building block of robust hydrogen-bonded 2D nets with coordinative saturation. Preservation of crystal structures upon guest alteration, guest removal, and host modification. J. Am. Chem. Soc. 124, 12453–12462 (2002)

    Article  Google Scholar 

  9. Desiraju, G.R.: Supramolecular synthons in crystal engineering–a new organic synthesis. Angew. Chem. Int. Ed. Engl. l34, 2311–2327 (1995)

    Article  Google Scholar 

  10. Hunter, C.A.: The role of aromatic interactions in molecular recognition. Chem. Soc. Rev. 23, 101–109 (1994)

    Article  Google Scholar 

  11. Avasthi, K., Kumar, A., Aswal, S., Kant, R., Raghunandan, R., Maulik, P.R., Khanna, R.S, Ravikumar, K.: Role of arene interactions and substituent effects in conformational (syn/anti) control of 1,2-diarylethanes. Cryst. Eng. Comm. 14, 383–388 (2012)

    Article  Google Scholar 

  12. Yadava, U., Singh, M., Roychoudhury, M.: Gas-phase conformational and intramolecular π–π interaction studies on some pyrazolo[3,4-d]pyrimidine derivatives. Comput. Theo. Chem. 977, 134–139 (2011)

    Article  Google Scholar 

  13. Gung, B.W., Emenike, B.U., Lewis, M., Kirschbaum, K.: Quantification of CH...π interactions: implications on how substituent effects influence aromatic interactions. Chem. Eur. J. 16, 12357–12362 (2010)

    Article  Google Scholar 

  14. Leonard, N.J.: Trimethylene bridges as synthetic spacers for the detection of intramolecular interactions. Acc. Chem. Res. 12, 423–429 (1979)

    Article  Google Scholar 

  15. Watt, M., Hardebeck, L.K.E., Kirkpatrick, C.C., Lewis, M.: Face-to-face arene-arene binding energies: dominated by dispersion but predicted by electrostatic and dispersion/polarizability substituent constants. J. Am. Chem. Soc. 133, 3854–3862 (2011)

    Article  Google Scholar 

  16. Wheeler, S.E.: Local nature of substituent effects in stacking interactions. J. Am. Chem. Soc. 133, 10262–10274 (2011)

    Article  Google Scholar 

  17. Hunter, C.A., Lawson, K.R., Urch, C.J.: Aromatic interactions. J. Chem. Soc. Perkin Trans. 2, 651–669 (2001)

    Google Scholar 

  18. Pickering, A.L., Seeber, G., Long, D.L., Cronin, L.: The importance of π–π, π–CH and N–CH interactions in the crystal packing of Schiff-base derivatives of cis,cis- and cis,trans-1,3,5-triaminocyclohexane. Cryst. Eng. Comm. 7, 504–510 (2005)

    Article  Google Scholar 

  19. Aravinda, S., Shamala, N., Das, C., Sriran**i, A., Karle, I.L., Balaram, P.: Aromatic-aromatic interactions in crystal structures of helical peptide scaffolds containing projecting phenylalanine residues. J. Am. Chem. Soc. 125, 5308–5315 (2003)

    Article  Google Scholar 

  20. Biswas, G., Chandra, T., Avasthi, K., Maulik, P.R.: 1,3-Bis[4,6-bis(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]propane. Acta Crystallogr. C51, 2453–2455 (1995)

    Google Scholar 

  21. Sutcliffe, E.Y., Zee-Cheng, K.Y., Cheng, C.C., Robins, R.K.: Potential purine antagonists. XXXII. The synthesis and antitumor activity of certain compounds related to 4-Aminopyrazolo[3,4-d]pyrimidine. J. Med. Chem. 5, 588–607 (1962)

    Article  Google Scholar 

  22. Bekhit, A.A., Abdel-Aziem, T.: Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agents. Bioorg. Med. Chem. 12, 1935–1945 (2004)

    Article  Google Scholar 

  23. Varnes, J.G., Wacker, D.A., Jacobson, I.C., Quan, M.L., Ellis, C.D., Rossi, K.A., He, M.Y., Luettgen, J.M., Knabb, R.M., Bai, S., He, K., Lam, P.Y.S., Wexler, R.R.: Design, structure–activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors. Bioorg. Med. Chem. Lett. 17, 6481–6488 (2007)

    Article  Google Scholar 

  24. Elion, G.B., Callahan, S.W., Nathan, H., Bieber, S., Rundles, R.W., Hilching, G.H.: Potentiation by inhibition of drug degradation: 6-substituted purines and xanthine oxidase. Biochem. Pharmacol. 12, 85–93 (1963)

    Article  Google Scholar 

  25. Schenone, S., Brullo, C., Musumeci, F., Botta, M.: Novel dual Src/ Abl inhibitors for hematologic and solid malignancies. Expert Opin. Investig. Drugs 19, 931–945 (2010)

    Article  Google Scholar 

  26. Carraro, F., Naldini, A., Pucci, A., Locatelli, G.A., Maga, G., Schenone, S., Bruno, O., Ranise, A., Bondavalli, F., Brullo, C., Fossa, P., Menozzi, G., Mosti, L., Modugno, M., Tintori, C., Manetti, F., Botta, M.: Pyrazolo[3,4-d]pyrimidine Inhibitors of c-Src Phosphorylation. J. Med. Chem. 49, 1549–1561 (2006)

    Article  Google Scholar 

  27. Indovina, P., Giorgi, F., Rizzo, V., Khadang, B., Schenone, S., Marzo, D., Forte, I.M., Tomei, V., Mattioli, E., Urso, V.D., Grilli, B., Botta, M., Giordano, A., Pentimalli, F.: New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization. Oncogenes 31(7), 929–938 (2012)

    Article  Google Scholar 

  28. Rossi, A., Schenone, S., Angelucci, A., Cozzi, M., Caracciolo, V., Pentimalli, F., Pucca, A., Pucci, B., Montagna, R.L., Bologna, M., Botta, M., Giordano, A.: New pyrazolo-[3,4-d]-pyrimidine derivative Src kinase inhibitors lead to cell cycle arrest and tumor growth reduction of human medulloblastoma cells. FASEB J. 24, 2881–2892 (2010)

    Article  Google Scholar 

  29. Carlomagno, F., Vitagliano, D., Guida, T., Basolo, F., Castellone, M.D., Melillo, R.M., Fusco, A., Santoro, M.: Efficient inhibition of RET/papillary thyroid carcinoma oncogenic kinases by 4-Amino-5-(4-Chloro-Phenyl)-7-(t-Butyl)Pyrazolo[3,4-d]Pyrimidine (PP2). J. Clin. Endocrinol. Metab. 88, 1897–1902 (2003)

    Article  Google Scholar 

  30. Kini, R.M.: Phospholipase A2: a complex multifunctional protein puzzle. In: Kini, R.M. (ed.) Venom Phospholipase A2 Enzymes: Structure, Function and Mechanism. Wiley, Chichester (1997)

    Google Scholar 

  31. Kini, R.M.: Structure–function relationships and mechanism of anticoagulant phospholipase A2 enzymes from snake venoms. Toxicon 45, 1147–1161 (2005)

    Article  Google Scholar 

  32. Singh, G., Gourinath, S., Sharma, S., Paramasivam, M., Srinivasan, A., Singh, T.P.: Sequence and crystal structure determination of a basic phospholipase A2 from common krait (Bungarus caeruleus) at 2.4A° resolution: identification and characterization of its pharmacological sites. J. Mol. Biol. 307, 1049–1059 (2001)

    Article  Google Scholar 

  33. Lok, S.M., Gao, R., Rouault, M., Lambeau, G., Gopalakrishnakone, P., Swaminathan, K.: Structure and function comparison of Micropechis ikaheka snake venom phospholipase A2 isoenzymes. FEBS J. 272, 1211–1220 (2005)

    Article  Google Scholar 

  34. Singh, N., Jabeen, T., Sharma, S., Somvanshi, R.K., Dey, S., Srinivasan, A., Singh, T.P.: Specific binding of non-steroidal anti-inflammatory drugs (NSAIDs) to phospholipase A2: structure of the complex formed between phospholipase A2 and diclofenac at 2.7A° resolution. Acta Crystallogr. D62, 410–416 (2006)

    Google Scholar 

  35. Singh, R.K., Vikram, P., Makker, J., Jabeen, T., Sharma, S., Dey, S., Kaur, P., Srinivasan, A., Singh, T.P.: Design of specific peptide inhibitors for group I phospholipase A2: structure of a complex formed between phospholipase A2 from Naja naja sagittifera (Group I) and a designed peptide inhibitor Val-Ala-Phe-Arg-Ser (VAFRS) at 1.9A° resolution reveals unique features. Biochemistry 42, 11701–11706 (2003)

    Article  Google Scholar 

  36. Yadava, U., Gupta, H.O., Roychoudhury, M.: A comparison of crystallographic and DFT optimized geometries on two taxane diterpenoids and docking studies with phospholipase A2. Med. Chem. Res. 21, 2162–2168 (2012)

    Article  Google Scholar 

  37. Jabeen, T., Singh, N., Singh, R.K., Sharma, S., Somvanshi, R.K., Dey, S., Singh, T.P.: Non-steroidal anti-inflammatory drugs as potent inhibitors of phospholipase A2: structure of the complex of phospholipase A2 with niflumi acid at 2.5A° resolution. Acta Crystallogr. D61, 1579–1586 (2005)

    Google Scholar 

  38. Boffa, M.C., Rothen, C., Verheij, H.M., Verger, R., DeHaas, G.H.: In: Eaker, D., Walstrom, T. (eds.) Natural Toxins, pp. 131–138. Pergamon Press, Oxford (1980)

    Google Scholar 

  39. Singh, N., Kumar, R.P., Kumar, S., Sharma, S., Mir, R., Kaur, P., Srinivasan, A., Singh, T.P.: Simultaneous inhibition of anti-coagulation and inflammation: crystal structure of phospholipase A2 complexed with indomethacin at 1.4A° resolution reveals the presence of the new common ligand-binding site. J. Mol. Recognit. 22, 437–445 (2009)

    Article  Google Scholar 

  40. Avasthi, K., Rawat, D.S., Maulik, P.R., Sarkhel, S., Broder, C.K., Howard, J.A.K.: 1H NMR and X-ray crystallographic analysis of 1,2-bis(4,6-diethylthio-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethane and its ‘propylene linker’-analog: molecular recognition versus crystal engineering. Tetrahedron Lett. 42, 7115–7117 (2001)

    Article  Google Scholar 

  41. Avasthi, K., Aswal, S., Kumar, R., Yadava, U., Rawat, D.S., Maulik, P.R.: Fine tuning of folded conformation by change of substituents: 1H NMR and crystallographic evidence for folded conformation due to arene interactions in pyrazolo[3,4-d]pyrimidine core-based ‘propylene linker’ compounds. J. Mol. Struct. 750, 179–185 (2005)

    Article  ADS  Google Scholar 

  42. Maulik, P.R., Avasthi, K., Biswas, G., Biswas, S., Rawat, D.S., Sarkhel, S., Chandra, T., Bhakuni, D.S.: A stacked pyrazolo[3,4-d]pyrimidine-based flexible molecule. Acta Crystallogr. C54, 275–277 (1998)

    Google Scholar 

  43. Avasthi, K., Aswal, S., Maulik, P.R.: A stacked pyrazolo[3,4-d]pyrimidine-based flexible molecule: the effect on stacking of an ethyl group in comparison with a methyl group. Acta Crystallogr. C57, 1324–1325 (2001)

    Google Scholar 

  44. Avasthi, K., Tewari, A., Rawat, D.S., Sharon, A., Maulik, P.R.: A stacked pyrazolo[3,4-d]pyrimidine-based flexible molecule: the effect of a bulky benzyl group on intermolecular stacking in comparison with methyl and ethyl groups. Acta Crystallogr. C58, o494–o495 (2002)

    Google Scholar 

  45. Avasthi, K., Farooq, S.M., Aswal, S., Raghunandan, R., Maulik, P.R.: 1H NMR and crystallographic evidence for tolerance of bulky electron withdrawing methanesulfonyl group on robustness of the U-motif in pyrazolo[3,4-d]pyrimidine core-based ‘Leonard linker’ compounds and formation of plus (+) motif. J. Mol. Struct. 827, 88–94 (2007)

    Article  ADS  Google Scholar 

  46. Avasthi, K., Bhagat, D., Bal, C., Sharon, A., Yadava, U., Maulik, P.R.: Unusual molecular conformation in dissymmetric propylene-linker compounds containing pyrazolo[3,4-d]pyrimidine and phthalimide moieties. Acta Crystallogr. C59, o409–o412 (2003)

    Google Scholar 

  47. Avasthi, K., Rawat, D.S., Sarkhel, S., Maulik, P.R.: A dimeric layered structure of a 4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine compound. Acta Crystallogr. C58, o325–o327 (2002)

    Google Scholar 

  48. Kennedy, T.: Managing the discovery/development interface. Drug Discov. Today 2, 436–444 (1997)

    Article  Google Scholar 

  49. DiMasi, J.A.: Success rates for new drugs entering clinical testing in the United States. Clin. Pharmacol. Ther. 58, 1–14 (1995)

    Article  Google Scholar 

  50. Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., Olson, A.J.: Autodock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem. 30, 2785–2791 (2009)

    Article  Google Scholar 

  51. Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R., Hart, W.E., Belew, R.K., Olson, A.J.: Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem. 19, 1639–1662 (1998)

    Article  Google Scholar 

  52. Friesner, R.A., Banks, J.L., Murphy, R.B., Halgren, T.A., Klicic, J.J., Mainz, D.T., Repasky, M.P., Knoll, E.H., Shelley, M., Perry, J.K., Shaw, D.E., Francis, P., Shenkin, P.S.: Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem. 47, 1739–1749 (2004)

    Article  Google Scholar 

  53. Glide: version 5.8 Schrödinger, LLC, New York (2012)

  54. Friesner, R.A., Murphy, R.B., Repasky, M.P., Frye, L.L., Greenwood, J.R., Halgren, T.A., Sanschagrin, P.C., Mainz, D.T.: Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem. 49, 6177–6196 (2006)

    Article  Google Scholar 

  55. Jorgenson, W.L., Maxwell, D.S., Tirado-Rives, J.: Development and testing of the OPLS all atom force field on conformational energetic and properties of organic liquids. J. Am. Chem. Soc. 118, 11225–11236 (1996)

    Article  Google Scholar 

  56. Sherman, W., Day, T., Jacobson, M.P., Friesner, R.A.: Novel procedure for modelling ligand/receptor induced fit effects. J. Med. Chem. 49, 534–553 (2006)

    Article  Google Scholar 

  57. Bissantz, C., Folkers, G., Rognan, D.: Protein-based virtual screening of chemical database. 1. Evaluation of different docking /scoring combinations. J. Med. Chem. 43, 4759–4767 (2000)

    Article  Google Scholar 

  58. QikProp: version 3.5 Schrödinger, LLC, New York (2012)

  59. Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J.: Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23, 3–25 (1997)

    Article  Google Scholar 

  60. Lipinski, C.A.: Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods 44, 235–249 (2000)

    Article  Google Scholar 

  61. Srivastava, H.K., Chourasia, M., Kumar, D., Sastry, G.N.: Comparison of computational methods to model DNA minor groove binders. J. Chem. Inf. Model. 51, 558–571 (2011)

    Article  Google Scholar 

  62. Srivastava, H.K., Sastry, G.N.: Molecular dynamics investigation on a series of HIV protease inhibitors: assessing the performance of MM-PBSA and MM-GBSA approaches. J. Chem. Inf. Model 52, 3088–3098 (2012)

    Article  Google Scholar 

  63. Kini, R.M., Evans, H.J.: Structure–function relationships of phospholipases. The anticoagulant region of phospholipases A2. J. Biol. Chem. 262, 14402–14407 (1987)

    Google Scholar 

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Acknowledgements

This work is supported by the Department of Science and Technology, Government of India through the FAST TRACK Scheme awarded to Dr. Umesh Yadava (Ref. No. SR/FT/CS-78/2010). The computational facility provided through FIST scheme to our department by DST, New Delhi, is also gratefully acknowledged.

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  1. Department of Physics, DDU Gorakhpur University, Gorakhpur, 273009, India

    Umesh Yadava, Maheshwer Singh & Mihir Roychoudhury

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  1. Umesh Yadava
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Yadava, U., Singh, M. & Roychoudhury, M. Pyrazolo[3,4-d]pyrimidines as inhibitor of anti-coagulation and inflammation activities of phospholipase A 2 : insight from molecular docking studies. J Biol Phys 39, 419–438 (2013). https://doi.org/10.1007/s10867-013-9299-7

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