International Journal of Life science and Pharma Reviews (IJLPR)  
  Aim and Scope - To publish peer reviewed review articles in rapidly developing field of Pharma and life sciences  
Pharmaceutical Sciences
Volume 12 Issue 3, May 2022    Pages:29-34
Ab Initio and DFT Investigation of Effect of Substituent at the C7 Position of 4-Amino-DANA Sialidase Inhibitor

Krishnan Chandrasekaran
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Sialic acid is the active site of neuraminidase protein, eventually it cleaves form its substrate via sialsyl cation intermediate and proliferates the viral infection to other cells. On account of weak binding affinity between substrate and receptor, the viral infection communicates to other cells and leads to mortality of humans. DANA is the first sialidase inhibitor formed by the dehydration of the C2 hydroxyl group of sialic acid.  The replacement of hydroxyl group at C4 position of DANA by an amino group drastically increases the binding affinity and results 4-amino-DANA inhibitor, which is potent than parent DANA.  Crystal structure of DANA shows that several binding sites remain free and it should be explored for more powerful sialidase inhibitors.  The current study systematically investigates the effect of substituent on the C7 position of 4-amino-DANA in gas phase and solvent phase as well.   X-Ray crystallographic study reveals that the C7 of glycerol side chain remains free.  Hence, substituent effect at C7 analysis is carried in search of potent sialidase inhibitors.  The ab initio and DFT investigation reveals that guanidino and methyl group at C7 position drastically increases the binding affinity between substrate and receptor. Hence further investigation of methyl and guanidine derivatives of the 4-amino-DANA could act as a promising candidate for the design and development of sialidase inhibitors.  Vaccination for the H1N1 is not effective due to the new viral mutagenic strains and hence, it cannot contain the viral infection. Therefore antiviral drugs will address the limitation of vaccination.  The current finding of sialidase antiviral inhibitors will effectively contain the viral infection and prevent the morbidity.
Keywords: Sialidase Inhibitors, 4-Amino-DANA, DFT, Binding Pocket
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  1. Sangma C, Hannongbua S. Structural information and computational methods used in design of neuraminidase inhibitors. Current Computer-Aided Drug Design. 2007 Jun 1;3(2):113-32.
  2. Gerdon AE, Wright DW, Cliffel DE. Hemagglutinin linear epitope presentation on monolayer-protected clusters elicits strong antibody binding. Biomacromolecules. 2005 Nov 14;6(6):3419-24.
  3. Jarreau PH, Harf A, Levame M, Lambré CR, Lorino H, Macquin-Mavier I. Effects of Neuraminidase on Airway Reactivity in the Guinea Pig1, 2. Am Rev Respir Dis. 1992;145:906-10.
  4. Holzer CT, Von Itzstein M, Jin B, Pegg MS, Stewart WP, Wu WY. Inhibition of sialidases from viral, bacterial and mammalian sources by analogues of 2-deoxy-2, 3-didehydro-N-acetylneuraminic acid modified at the C-4 position. Glycoconjugate journal. 1993 Feb;10(1):40-4.
  5. Chandrasekaran K.  Abintio and DFT investigation of C4 and C7 position of sialidase anti-viral inhibitor,  Journal of Chemical and Pharmaceutical Research, 2015 Aug; 7(4): 425-430.
  6. Karplus PA, Faerman C. Ordered water in macromolecular structure. Current opinion in structural biology. 1994 Oct 1;4(5):770-6.
  7. Goodford PJ. A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. Journal of medicinal chemistry. 1985 Jul;28(7):849-57.
  8. Kim CU, Lew W, Williams MA, Liu H, Zhang L, Swaminathan S, Bischofberger N, Chen MS, Mendel DB, Tai CY, Laver WG. Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. Journal of the American Chemical Society. 1997 Jan 29;119(4):681-90.
  9. Chong AK, Pegg MS, Taylor NR, Von ItzsteiN M. Evidence for a sialosylcation transition?state complex in the reaction of sialidase from influenza virus. European journal of biochemistry. 1992 Jul;207(1):335-43.
  10. Chandrasekaran, K. Quantum chemical investigation of C12 and C6 position of Oseltamivirsialidase antiviral inhibitor, Journal of Applied Pharmaceutical Science,    2015; 5(09): 120-123.
  11. Stoll V, Stewart KD, Maring CJ, Muchmore S, Giranda V, Gu YG, Wang G, Chen Y, Sun M, Zhao C, Kennedy AL. Influenza neuraminidase inhibitors: structure-based design of a novel inhibitor series. Biochemistry. 2003 Jan 28;42(3):718-27.
  12. AndzelmJ,  Kolmel C,  Klamt A, et al. Incorporation of solvent effects into density functional calculations of molecular energies and geometries.  Journal of Chemical. Physics, 1995; 103: 9312-9315.
  13. Hemalatha K, Chakkaravarthi V, Murthy KG, Kayatri R, Girija K. Molecular Properties and Docking Studies of Benzimidazole Derivatives as Potential Peptide Deformylase Inhibitors. Asian Journal of Research in Chemistry. 2014;7(7):644-8.
  14. Sarika V. Khandbahale, Kanchan R. Pagar, Rupali. V. Khankari. Introduction to Enzymes. Asian J. Res. Pharm. Sci. 2019; 9(2):123-130.
  15. Faust R, Garratt PJ, Pérez MA, Piccio VJ, Madsen C, Stenstrøm A, Frølund B, Davidson K, Teh MT, Sugden D. 7-Substituted-melatonin and 7-substituted-1-methylmelatonin analogues: Effect of substituents on potency and binding affinity. Bioorganic & medicinal chemistry. 2007 Jul 1;15(13):4543-51.
  16. Smith BJ, Colman PM, Von Itzstein M, Danylec B, Varghese JN. Analysis of inhibitor binding in influenza virus neuraminidase. Protein Science. 2001 Apr;10(4):689-96.
  17. Kairys V, Baranauskiene L, Kazlauskiene M, Matulis D, Kazlauskas E. Binding affinity in drug design: experimental and computational techniques. Expert opinion on drug discovery. 2019 Aug 3;14(8):755-68.
  18. Khade S, Pallavi MP. A Computational Study Of Molecular Docking For Antiviral Compounds Against Sars-Cov-2. Int J Pharm Bio Sci. 2022 Jan;13(1):37-51.
  19. Alyar S, ?en T, Özmen ÜÖ, Alyar H, Adem ?, ?en C. Synthesis, spectroscopic characterizations, enzyme inhibition, molecular docking study and DFT calculations of new Schiff bases of sulfa drugs. Journal of Molecular Structure. 2019 Jun 5;1185:416-24.
  20. Nadzirin IA, Chor AL, Salleh AB, Rahman MB, Tejo BA. Discovery of new inhibitor for the protein arginine deiminase type 4 (PAD4) by rational design of α-enolase-derived peptides. Computational Biology and Chemistry. 2021 Jun 1;92:107487.
  21. Chandrasekaran K. Investigation of solvation dynamics and Hydration pattern of sialic acid by ab initio and DF method. Int J. Pharm Sci Res. 2020 May;11(5):2482-2488.
  22. Magee CA, Peterson LW, Cafiero M, Selner EF. The effects of ligand charge, orientation and size on the binding of potential inhibitors for aldehyde dehydrogenase. Computational and Theoretical Chemistry. 2020 Sep 1;1185:112868.
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