Advertisement

Structure-aided drug development of potential neuraminidase inhibitors against pandemic H1N1 exploring alternate binding mechanism

  • Khushboo D. Malbari
  • Anand S. Chintakrindi
  • Lata R. Ganji
  • Devanshi J. Gohil
  • Sweta T. Kothari
  • Mamata V. Joshi
  • Meena A. KanyalkarEmail author
Original Article
First Online:

Abstract

The rate of mutability of pathogenic H1N1 influenza virus is a threat. The emergence of drug resistance to the current competitive inhibitors of neuraminidase, such as oseltamivir and zanamivir, attributes to a need for an alternative approach. The design and synthesis of new analogues with alternate approach are particularly important to identify the potential neuraminidase inhibitors which may not only have better anti-influenza activity but also can withstand challenge of resistance. Five series of scaffolds, namely aurones (1a–1e), pyrimidine analogues (2a–2b), cinnamic acid analogues (3a–3k), chalcones (4a–4h) and cinnamic acid linkages (5a–5c), were designed based on virtual screening against pandemic H1N1 virus. Molecular modelling studies revealed that the designed analogues occupied 430-loop cavity of neuraminidase. Docking of sialic acid in the active site preoccupied with the docked analogues, i.e. in 430-loop cavity, resulted in displacement of sialic acid from its native pose in the catalytic cavity. The favourable analogues were synthesized and evaluated for the cytotoxicity and cytopathic effect inhibition by pandemic H1N1 virus. All the designed analogues resulting in displacement of sialic acid suggested alternate binding mechanism. Overall results indicated that aurones can be measured best among all as potential neuraminidase inhibitor against pandemic H1N1 virus.

Graphical abstract

Keywords

Pandemic H1N1 Scaffolds Molecular modelling 430-Loop cavity Sialic acid displacement Cytopathic effect inhibition Alternate binding mechanism 

Abbreviations

CC

Cell control

CPE

Cytopathic effect

DCC

N,N′-Dicyclohexylcarbodiimide

DCM

Dichloromethane

DMF

Dimethyl formamide

DMSO

Dimethylsulfoxide

DS

Discovery studio

FBS

Foetal bovine serum

HA

Haemagglutinin

LR

Laboratory reagent

MDCK

Madin-Darby canine kidney cells

MEM

Minimum essential medium

NA

Neuraminidase

NCDC

National Centre for Disease Control

OMV

Oseltamivir

SA

Sialic acid

TEA

Triethylamine

VC

Virus control

WHO

World Health Organization

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

Notes

Acknowledgements

M. A. Kanyalkar thanks Indian Council of Medical Research (ICMR), New Delhi, for funding computational facilities at Prin. K. M. Kundnani College of Pharmacy through Adhoc research scheme (58/36/2013-BMS). K. D. Malbari thanks ICMR, New Delhi, for Senior Research Fellowship (58/36/2013-BMS). A. S. Chintakrindi also thanks ICMR, New Delhi, for Senior Research Fellowship (58/27/2007-BMS). K. D. Malbari, D. J. Gohil and S. T. Kothari acknowledge National Centre for Disease Control (NCDC), New Delhi, for providing Madin-Darby canine kidney (MDCK) cell line and thank Haffkine Institute for providing Pandemic Influenza A (H1N1) Mumbai Isolate for cytopathic effect inhibition assay. M. V. Joshi acknowledges National NMR Facility provided by TIFR, Colaba.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

11030_2019_9919_MOESM1_ESM.tif (26 mb)
Supplementary Fig. MDCK cells without infection (CC) and with infection (VC1–VC4) observed for three days (TIFF 26594 kb)
11030_2019_9919_MOESM2_ESM.docx (28 kb)
Supplementary material 2 (DOCX 28 kb)
11030_2019_9919_MOESM3_ESM.docx (13.2 mb)
Supplementary material 3 (DOCX 13545 kb)

References

  1. 1.
    Liu C, Eichelberger MC, Compans RW, Air GM (1995) Influenza type A virus neuraminidase does not play a role in viral entry, replication, assembly, or budding. J Virol 69:1099–1106Google Scholar
  2. 2.
    Palese P, Tobita K, Ueda M, Compans RW (1974) Characterization of temperature sensitive influenza virus mutants defective in neuraminidase. Virology 61:397–410CrossRefGoogle Scholar
  3. 3.
    De Clercq E (2006) Antiviral agents active against influenza A viruses. Nat Rev Drug Discov 5:1015–1025.  https://doi.org/10.1038/nrd2175 CrossRefGoogle Scholar
  4. 4.
    Hayden FG, de Jong MD (2011) Emerging influenza antiviral resistance threats. J Infect Dis 203:6–10CrossRefGoogle Scholar
  5. 5.
    Trebbien R, Pedersen SS, Vorborg K et al (2017) Development of oseltamivir and zanamivir resistance in influenza A(H1N1)pdm09 virus, Denmark, 2014. Eurosurveillance 22Google Scholar
  6. 6.
    Williamson JC, Pegram PS (2000) Respiratory distress associated with zanamivir. N Engl J Med 342:661–662CrossRefGoogle Scholar
  7. 7.
    Kim CU, Chen X, Mendel DB (1999) Neuraminidase inhibitors as anti-influenza virus agents. Antivir Chem Chemother 10:141–154.  https://doi.org/10.1177/095632029901000401 CrossRefGoogle Scholar
  8. 8.
    Dao T-T, Tung B-T, Nguyen P-H et al (2010) C-Methylated flavonoids from Cleistocalyx operculatus and their inhibitory effects on novel influenza A (H1N1) neuraminidase. J Nat Prod 73:1636–1642.  https://doi.org/10.1021/np1002753 CrossRefGoogle Scholar
  9. 9.
    Dao TT, Nguyen PH, Lee HS et al (2011) Chalcones as novel influenza A (H1N1) neuraminidase inhibitors from Glycyrrhiza inflata. Bioorg Med Chem Lett 21:294–298.  https://doi.org/10.1016/j.bmcl.2010.11.016 CrossRefGoogle Scholar
  10. 10.
    Ryu YB, Kim JH, Park S-J et al (2010) Inhibition of neuraminidase activity by polyphenol compounds isolated from the roots of Glycyrrhiza uralensis. Bioorg Med Chem Lett 20:971–974.  https://doi.org/10.1016/j.bmcl.2009.12.106 CrossRefGoogle Scholar
  11. 11.
    Nguyen TNA, Dao TT, Tung BT, Choi H, Kim E, Park J et al (2010) Influenza A (H1N1) neuraminidase inhibitors from Vitis amurensis. Food Chem 124(2):437–443.  https://doi.org/10.1016/j.foodchem.2010.06.049 CrossRefGoogle Scholar
  12. 12.
    Chintakrindi AS, Gohil DJ, Kothari ST et al (2018) Design, synthesis and evaluation of chalcones as H1N1 Neuraminidase inhibitors. Med Chem Res 27:1013–1025.  https://doi.org/10.1007/s00044-017-2124-2 CrossRefGoogle Scholar
  13. 13.
    Malbari K, Gonsalves H, Chintakrindi A et al (2018) In search of effective H1N1 neuraminidase inhibitor by molecular docking, antiviral evaluation and membrane interaction studies using NMR. Acta Virol 62:179–190.  https://doi.org/10.4149/av_2018_209 CrossRefGoogle Scholar
  14. 14.
    Suruse P, Malbari K, Chintakrindi A, Gohil D, Srivastava S, Kothari S, Chowdhary A, Meena K (2016) Virucidal activity of newly synthesized chalcone derivatives against H1N1 virus supported by molecular docking and membrane interaction studies. J Antivir Antiretrovir 8:79–89Google Scholar
  15. 15.
    Zhou B, Xing C (2015) Diverse molecular targets for chalcones with varied bioactivities. Med Chem (Los Angeles) 5:388–404CrossRefGoogle Scholar
  16. 16.
    Detsi A, Majdalani M, Kontogiorgis CA et al (2009) Natural and synthetic 2′-hydroxy-chalcones and aurones: synthesis, characterization and evaluation of the antioxidant and soybean lipoxygenase inhibitory activity. Bioorg Med Chem 17:8073–8085.  https://doi.org/10.1016/j.bmc.2009.10.002 CrossRefGoogle Scholar
  17. 17.
    Morales-Camilo N, Salas CO, Sanhueza C et al (2015) Synthesis, biological evaluation, and molecular simulation of chalcones and aurones as selective MAO-B inhibitors. Chem Biol Drug Des 85:685–695.  https://doi.org/10.1111/cbdd.12458 CrossRefGoogle Scholar
  18. 18.
    Gravina HD, Tafuri NF, Silva Júnior A et al (2011) In vitro assessment of the antiviral potential of trans-cinnamic acid, quercetin and morin against equid herpesvirus 1. Res Vet Sci 91:e158–e162.  https://doi.org/10.1016/j.rvsc.2010.11.010 CrossRefGoogle Scholar
  19. 19.
    Stankyavichyus AP, Stankyavichene LMM, Sapragonene MS et al (1988) Synthesis and antiviral activity of cinnamic acid derivatives. Pharm Chem J 22:896–900.  https://doi.org/10.1007/BF00771641 Google Scholar
  20. 20.
    Amano R, Yamashita A, Kasai H et al (2017) Cinnamic acid derivatives inhibit hepatitis C virus replication via the induction of oxidative stress. Antivir Res 145:123–130.  https://doi.org/10.1016/j.antiviral.2017.07.018 CrossRefGoogle Scholar
  21. 21.
    An J, Lee DCW, Law AHY et al (2009) A novel small-molecule inhibitor of the avian influenza H5N1 virus determined through computational screening against the neuraminidase. J Med Chem 52:2667–2672.  https://doi.org/10.1021/jm800455g CrossRefGoogle Scholar
  22. 22.
    Kudi AC, Myint SH (1999) Antiviral activity of some Nigerian medicinal plant extracts. J Ethnopharmacol 68:289–294CrossRefGoogle Scholar
  23. 23.
    Discovery Studio, 3.1; Accelrys Inc. San DiegoGoogle Scholar
  24. 24.
    Morris GM, Huey R, Lindstrom W et al (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791.  https://doi.org/10.1002/jcc.21256 CrossRefGoogle Scholar
  25. 25.
    Vavricka CJ, Li Q, Wu Y et al (2011) Structural and functional analysis of laninamivir and its octanoate prodrug reveals group specific mechanisms for influenza NA inhibition. PLoS Pathog 7:e1002249.  https://doi.org/10.1371/journal.ppat.1002249 CrossRefGoogle Scholar
  26. 26.
    Rizvi SMD, Shakil S, Haneef M (2013) A simple click by click protocol to perform docking: AutoDock 4.2 made easy for non-bioinformaticians. EXCLI J. 12:831–857Google Scholar
  27. 27.
    Suite, Samll-Molecule Drug Discovery (2013) QikProp, version 3.3, User Manual, Schrodinger, LLC, New York, NY2013Google Scholar
  28. 28.
    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefGoogle Scholar
  29. 29.
    Itzstein M von, Thomson R (2009) Anti-influenza drugs: the development of sialidase inhibitors BT—Antiviral strategies. In: Kräusslich H-G, Bartenschlager R (eds) Handbook of experimental pharmacology, vol 189. Springer, Berlin, pp 111–154Google Scholar
  30. 30.
    Chintakrindi A, D’souza C, Kanyalkar M (2012) Rational development of neuraminidase inhibitor as novel anti-flu drug. Mini-Rev Med Chem 12:1273–1281CrossRefGoogle Scholar
  31. 31.
    Li Q, Qi J, Zhang W et al (2010) The 2009 pandemic H1N1 neuraminidase N1 lacks the 150-cavity in its active site. Nat Struct Mol Biol 17:1266CrossRefGoogle Scholar
  32. 32.
    Lentz MR, Webster RG, Air GM (1987) Site-directed mutation of the active site of influenza neuraminidase and implications for the catalytic mechanism. Biochemistry 26:5351–5358.  https://doi.org/10.1021/bi00391a020 CrossRefGoogle Scholar
  33. 33.
    Gleeson MP, Hersey A, Hannongbua S (2011) In-silico ADME models: a general assessment of their utility in drug discovery applications. Curr Top Med Chem 11:358–381CrossRefGoogle Scholar
  34. 34.
    Dunn WJ, Koehler MG, Grigoras S (1987) The role of solvent-accessible surface area in determining partition coefficients. J Med Chem 30:1121–1126.  https://doi.org/10.1021/jm00390a002 CrossRefGoogle Scholar
  35. 35.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25.  https://doi.org/10.1016/S0169-409X(96)00423-1 CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical ChemistryPrin. K. M. Kundnani College of PharmacyCuffe ParadeIndia
  2. 2.Haffkine Institute for Training, Research and TestingParelIndia
  3. 3.National Facility for High Field NMRTata Institute of Fundamental ResearchColabaIndia

Personalised recommendations

Cite article

Buy options