Skip to main content

Advertisement

Log in

Computational exploration and experimental validation to identify a dual inhibitor of cholinesterase and amyloid-beta for the treatment of Alzheimer’s disease

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

Abstract

The cholinesterases are essential targets implicated in the pathogenesis of Alzheimer’s disease (AD). In the present study, virtual screening and molecular docking are performed to identify the potential hits. Docking-post processing (DPP) and pose filtration protocols against AChE and BChE resulted in three hits (AW00308, HTS04089, and JFD03947). Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) and molecular dynamics simulation analysis affirmed the stability and binding pattern of the docked complex JFD03947, which was further synthesized and evaluated for in vitro cholinesterase inhibition (AChE, IC50 = 0.062 µM; BChE, IC50 = 1.482 µM) activity. The enzyme kinetics study of the JFD03947 against hAChE and hBChE suggested a mixed type of inhibition. The results of thioflavin T-assay also elicited anti-Aβ aggregation activity by JFD03947. Further, biological evaluation of identified compound JFD03947 also showed neuroprotective ability against the SH-SY5Y neuroblastoma cell lines.

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

Access this article

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
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Scheme 1
Fig. 12
Fig. 13
Fig. 14
Fig. 15

Similar content being viewed by others

References

  1. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC (2011) Alzheimer’s Dementia 7(3):270

    PubMed  PubMed Central  Google Scholar 

  2. Darras FH, Pockes S, Huang G, Wehle S, Strasser A, Wittmann H-J, Nimczick M, Sotriffer CA, Decker M (2014) ACS Chem Neurosci 5(3):225

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Sharma P, Tripathi A, Tripathi PN, Prajapati SK, Seth A, Tripathi MK, Srivastava P, Tiwari V, Krishnamurthy S, Shrivastava SK (2019) Eur J Med Chem 167:510

    CAS  PubMed  Google Scholar 

  4. Wilson RS, Leurgans SE, Boyle PA, Bennett DA (2011) Arch Neurol 68(3):351

    PubMed  PubMed Central  Google Scholar 

  5. Tripathi PN, Srivastava P, Sharma P, Tripathi MK, Seth A, Tripathi A, Rai SN, Singh SP, Shrivastava SK (2019) Bioorg Chem 85:82

    CAS  PubMed  Google Scholar 

  6. Klimova B, Maresova P, Valis M, Hort J, Kuca K (2015) Clin Interv Aging 10:1401

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Shrivastava SK, Sinha SK, Srivastava P, Tripathi PN, Sharma P, Tripathi MK, Tripathi A, Choubey PK, Waiker DK, Aggarwal LM (2019) Bioorg Chem 82:211

    CAS  PubMed  Google Scholar 

  8. Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, Luchsinger JA, Ogunniyi A, Perry EK, Potocnik F (2008) Lancet Neurol 7(9):812

    PubMed  PubMed Central  Google Scholar 

  9. Iqbal K, Grundke-Iqbal I (2010) Alzheimer’s disease, a multifactorial disorder seeking multitherapies. Elsevier, New York

    Google Scholar 

  10. Sharma P, Tripathi A, Tripathi PN, Singh SS, Singh SP, Shrivastava SK (2019) ACS Chem Neurosci 10(10):4361

    CAS  PubMed  Google Scholar 

  11. Ferreira Neto DC, Alencar Lima J, Sobreiro Francisco Diz de Almeida J, Costa França TC, Jorge do Nascimento C, Figueroa Villar JD (2018) J Biomol Struct Dyn 36(15):4099

  12. Mishra P, Sharma P, Tripathi PN, Gupta SK, Srivastava P, Seth A, Tripathi A, Krishnamurthy S, Shrivastava SK (2019) Bioorg Chem 89:103025

    CAS  PubMed  Google Scholar 

  13. Tripathi PN, Srivastava P, Sharma P, Seth A, Shrivastava SK (2019) Biorg Med Chem 27(7):1327

    CAS  Google Scholar 

  14. Xu Y, Cheng S, Sussman JL, Silman I, Jiang H (2017) Molecules 22(8):1324

    PubMed Central  Google Scholar 

  15. Srivastava P, Tripathi PN, Sharma P, Rai SN, Singh SP, Srivastava RK, Shankar S, Shrivastava SK (2019) Eur J Med Chem 163:116

    CAS  PubMed  Google Scholar 

  16. Srivastava P, Tripathi PN, Sharma P, Shrivastava SK (2019) Biorg Med Chem 27(16):3650

    CAS  Google Scholar 

  17. Tripathi A, Choubey PK, Sharma P, Seth A, Saraf P, Shrivastava SK (2020) Bioorg Chem 95:103506

    CAS  PubMed  Google Scholar 

  18. Sharma P, Tripathi MK, Shrivastava SK (2020) Cholinesterase as a target for drug development in Alzheimer’s disease. Methods Mol Biol 2089:257–286

    CAS  PubMed  Google Scholar 

  19. Schelterns P, Feldman H (2003) Lancet Neurol 2(9):539

    Google Scholar 

  20. Eskander MF, Nagykery NG, Leung EY, Khelghati B, Geula C (2005) Brain Res 1060(1–2):144

    CAS  PubMed  Google Scholar 

  21. Santarpia L, Grandone I, Contaldo F, Pasanisi F (2013) J Cachexia Sarcopenia Muscle 4(1):31

    PubMed  Google Scholar 

  22. Hartmann J, Kiewert C, Duysen EG, Lockridge O, Greig NH, Klein J (2007) J Neurochem 100(5):1421

    CAS  PubMed  Google Scholar 

  23. Manoharan I, Boopathy R, Darvesh S, Lockridge O (2007) Clin Chim Acta 378(1–2):128

    CAS  PubMed  Google Scholar 

  24. Greig NH, Utsuki T, Yu Q-s, Zhu X, Holloway HW, Perry T, Lee B, Ingram DK, Lahiri DK (2001) Curr Med Res Opin 17(3):159

    CAS  PubMed  Google Scholar 

  25. Lane RM, Potkin SG, Enz A (2006) Int J Neuropsychopharmacol 9(1):101

    CAS  PubMed  Google Scholar 

  26. Perry EK, Perry R, Blessed G, Tomlinson B (1978) Neuropathol Appl Neurobiol 4(4):273

    CAS  PubMed  Google Scholar 

  27. Bullock R, Lane R (2007) Curr Alzheimer Res 4(3):277

    CAS  PubMed  Google Scholar 

  28. Sharma P, Srivastava P, Seth A, Tripathi PN, Banerjee AG, Shrivastava SK (2019) Prog Neurobiol 174:53

    CAS  PubMed  Google Scholar 

  29. Smith MA, Rottkamp CA, Nunomura A, Raina AK, Perry G (2000) Biochim Biophys Acta (BBA). Basis of Disease 1502(1):139

    CAS  Google Scholar 

  30. Inestrosa NC, Dinamarca MC, Alvarez A (2008) FEBS J 275(4):625

    CAS  PubMed  Google Scholar 

  31. Inestrosa NC, Alvarez A, Perez CA, Moreno RD, Vicente M, Linker C, Casanueva OI, Soto C, Garrido J (1996) Neuron 16(4):881

    CAS  PubMed  Google Scholar 

  32. Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W (2013) J Comput Aided Mol Des 27(3):221

    PubMed  Google Scholar 

  33. Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W (2010) J Chem Theory Comput 6(5):1509

    CAS  PubMed  Google Scholar 

  34. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) J Med Chem 49(21):6177

    CAS  PubMed  Google Scholar 

  35. Jacobson MP, Pincus DL, Rapp CS, Day TJ, Honig B, Shaw DE, Friesner RA (2004) Proteins 55(2):351

    CAS  PubMed  Google Scholar 

  36. MacKerell AD Jr, Bashford D, Bellott M, Dunbrack RL Jr, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S (1998) J Phys Chem B 102(18):3586

    CAS  PubMed  Google Scholar 

  37. Heindel ND, Lemke SM, Fish VB (1967) J Chem Eng Data 12(4):596

    CAS  Google Scholar 

  38. Ellman GL, Courtney KD, Andres V Jr, Featherstone RM (1961) Biochem Pharmacol 7(2):88

    CAS  PubMed  Google Scholar 

  39. Peauger L, Azzouz R, Gembus V, Tintas M-L, Sopková-de Oliveira Santos J, Bohn P, Papamicaël C, Levacher V (2017) J Med Chem 60(13):5909

    CAS  PubMed  Google Scholar 

  40. Lineweaver H, Burk D (1934) J Am Chem Soc 56(3):658

    CAS  Google Scholar 

  41. Dixon M (1972) Biochem J 129(1):197

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Levine IIIH (1993) Protein Sci 2(3):404

    CAS  PubMed  PubMed Central  Google Scholar 

  43. More SS, Vince R (2012) ACS Chem Neurosci 3(3):204

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kontoyianni M, McClellan LM, Sokol GS (2004) J Med Chem 47(3):558

    CAS  PubMed  Google Scholar 

  45. Wang R, Lu Y, Wang S (2003) J Med Chem 46(12):2287

    CAS  PubMed  Google Scholar 

  46. Kryger G, Silman I, Sussman JL (1999) Structure 7(3):297

    CAS  PubMed  Google Scholar 

  47. Cheung J, Rudolph MJ, Burshteyn F, Cassidy MS, Gary EN, Love J, Franklin MC, Height JJ (2012) J Med Chem 55(22):10282

    CAS  PubMed  Google Scholar 

  48. Dighe SN, De la Mora E, Chan S, Kantham S, McColl G, Miles JA, Veliyath SK, Sreenivas BY, Nassar ZD, Silman I (2019) Commun Chem 2(1):1

    CAS  Google Scholar 

  49. Carmo Carreiras M, Mendes E, Jesus Perry M, Paula Francisco A, Marco-Contelles J (2013) Curr Top Med Chem 13(15):1745

    PubMed  Google Scholar 

  50. Cacabelos R (2007) Neuropsychiatr Dis Treat 3(3):303

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Agatonovic-Kustrin S, Kettle C, Morton DW (2018) Biomed Pharmacother 106:553

    CAS  PubMed  Google Scholar 

  52. Goodman LS (1996) Goodman and Gilman’s the pharmacological basis of therapeutics. McGraw-Hill, New York

    Google Scholar 

  53. Silva MA, Kiametis AS, Treptow W (2020). J Chem Inf Model. https://doi.org/10.1021/acs.jcim.9b01073

    Article  PubMed  Google Scholar 

  54. Schneider LS (2000) Dialogues Clin Neurosci 2(2):111

    Google Scholar 

  55. Kandiah N, Pai M-C, Senanarong V, Looi I, Ampil E, Park KW, Karanam AK, Christopher S (2017) Clin Interv Aging 12:697

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Luo W, Su Y-B, Hong C, Tian R-G, Su L-P, Wang Y-Q, Li Y, Yue J-J, Wang C-J (2013) Bioorg Med Chem 21(23):7275

    CAS  PubMed  Google Scholar 

  57. Gao X-h, Liu L-b, Liu H-r, Tang J-j, Kang L, Wu H, Cui P, Yan J (2018) J Enzyme Inhib Med Chem 33(1):110

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge to Indian Institute of Technology (BHU) for providing financial assistance through postdoctoral fellowship (Grant No. PDF/007/15-16/16-17). The authors are also thankful to the Department of Health Research, Ministry of Health and Family Welfare for providing the Young Scientist Project in newer areas of Drugs Chemistry (DHR/HRD/YS-15-2015-16).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sushant Kumar Shrivastava.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

Below is the link to the electronic supplementary material

Supplementary material 1 (DOCX 5851 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tripathi, M.K., Sharma, P., Tripathi, A. et al. Computational exploration and experimental validation to identify a dual inhibitor of cholinesterase and amyloid-beta for the treatment of Alzheimer’s disease. J Comput Aided Mol Des 34, 983–1002 (2020). https://doi.org/10.1007/s10822-020-00318-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-020-00318-w

Keywords

Navigation