ZIKA VIRUS SERENE PROTEASE COMPLEX (NS2B-NS3) INHIBITION BY 2-AMINO-5-{[(1Z)-AMINO({[(Z)-BENZOYL]IMINO})METHYL]AMINO}-N-(5-AMINO-7-{[CARBAMOYL(PHENYL)METHYL]AMINO}-6-OXOHEPTYL)PENTANAMIDE, IN SILICO STUDIES

  • Kalpana Virendra Singh Govt. Madhav Science P.G.College Ujjain M.P. India
  • Ramchander Merugu DEPARTMENT OF BIOCHEMISTRY, MAHATMA GANDHI UNIVERSITY, NALGONDA, TELANGANA, INDIA-508254
  • Jeeven Singh Solanki Govt. Madhav Science P.G.College Ujjain M.P. India

Abstract

Objective: The present in silico study is taken to report 2-amino-5-{[(1Z) -amino ({[(Z) -benzoyl] imino}) methyl] amino} -N-(5-amino-7-{[carbamoyl (phenyl) methyl] amino} -6-oxoheptyl) pentanamide as Zika virus (ZIKV) NS2B-NS3 protease inhibitor.

Methods: In silico studies performed on online docking servers. NS2B-NS3 serine protease from ZIKV with PDB ID: 5GJ4 a hydrolase with total structure weight of 102878.54 is selected as the target. Docking server is used for carrying out docking calculations. Lamarckian genetic algorithm and the Solis and Wets local search methods are used for performing docking simulations. Free energy calculations, hydrogen bond (HB) formation, polar and hydrophobic interactions and HB plot are studied in this study.

Results: Binding pocket is found on a serine protease NS2B chain A. Binding site predictions propose NKK as the suitable ligand for binding, which has structure closely related to the proposed ligand2-amino-5-{[(1Z) -amino ({[(Z) -benzoyl] imino}) methyl] amino} -N-(5-amino-7-{[carbamoyl (phenyl) methyl] amino} -6-oxoheptyl) pentanamide. Free energy of binding is - 4.08 kcal/Mol and inhibition constant (Ki) is very less 1.02 mm. The ligand binds to chain A of NS2B and chain B of NS3 serine protease. The legend is bound to serine protease complex through strong HB, formed between THR 60 (A) and N6 of ligand, GLU62 (A) and N8 of ligand, ARG 55 (A) and N3 of ligand and ASN108 (B) and N7 of ligand apart from polar and hydrophobic interactions.

Conclusion: Docking studies performed establishes the proposed ligand2-amino-5-{[(1Z)-amino ({[(Z)-benzoyl] imino}) methyl] amino} -N-(5- amino-7-{[carbamoyl (phenyl) methyl] amino}-6-oxoheptyl) pentanamide as a molecule which can be used for the inhibition of ZIKV NS2B-NS3 serine protease.

  

Keywords: Zika virus, NS2B-NS3 protease, Inhibition, In silico.

Author Biographies

Kalpana Virendra Singh, Govt. Madhav Science P.G.College Ujjain M.P. India

Department of Higher Education, Govt. of Madhya Pradesh

ASSTT. PROFESSOR 

Ramchander Merugu, DEPARTMENT OF BIOCHEMISTRY, MAHATMA GANDHI UNIVERSITY, NALGONDA, TELANGANA, INDIA-508254

DEPARTMENT OF BIOCHEMISTRY, MAHATMA GANDHI UNIVERSITY, NALGONDA, TELANGANA, INDIA-508254

 

Jeeven Singh Solanki, Govt. Madhav Science P.G.College Ujjain M.P. India

Department of Higher Education, Govt. of Madhya Pradesh

ASSTT. PROFESSOR 

References

1.W.G.Bearcroft,Zika virus infection experimentally induced in a human volunteer. Trans.R.Soc.Trop. Med.Hyg.1956;50:442-448.
2.V.M.Cao-Lormeau, et.al,Guillain-Barre Syndrome outbreak associated with Zika virus infection in French Polynesia: A case- control study.Lancet 2016; 387:1531-1539.
3.L.Schuler-Faccini,et.al.,Possible association between Zika virus infection and microcephaly-Brazil,2015.MMWR Morb. Mortal.Wkly.Rep.2016; 65:59-62.
4.T.C.Pierson,M.S.Diamond, in Fields Virology.Lippincott-Raven Publishers, ed.6,chap.2013; 26:747-794.
5.Chapter in a book: D.Lindenbach,C.L.Murray,H.-J.Thiel,C.M.Rice, in fields Virology. 6th ed. Lippincott-Raven Publishers:2013; 712-746.
6.D.L.Heymann,A.Hodgson,A.A.Sall,D.O.Freedman,J.E.Staples,F. Althabe,K.Baruah, G.Mahmud,N.Kandun,P.F.Vasconcelos,S.Bino,K.U.Menon,Zika virus and microcephaly: Why is this situation a PHEIC?Lancet 2016; 387:719-721.
7.S.C.Weaver, et.al.,Zika virus: History, emergence, biology and prospects for control. Antiviral Res.2016;130: 69-80.
8.S.Ekins,et.al..Open drug discovery for the Zika vius.F1000 Research2016; 5: 150.
9.C.Nitsche et.al., Biochemistry and medicinal chemistry of the dengue virus protease.Chem.Rev.2014;114: 11348-11381.
10.D.Luo,S,G,Vasudevan,J.Lescar, The flavivirus NS2B-NS3 Protease-helicase as a target for antiviral drug development. Antiviral Res.2015;118: 148-158. 11.B.Falgout,M.Pethel,Y.M.Zhang, C.J.Lai, Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins.J.Virol.1991; 65: 2467-2475.
12.T.J.Chambers,et.al.,Evidence that the N-terminal domain of nonstructural protein NS3 from yellow fever virus is a serine protease responsible for site-specific cleavages in the viral polyprotein.Proc.Natl.Acad.Sci.U.S.A.1990; 87: 8898-8902.
13.D.Leung, et.al.,Activity of recombinant dengue 2 virus NS3 protease in the presence of a truncated NS2B co-factor, small peptide substrates, and inhibitors.J.Biol.Chem.2001;276: 45762-45771.
14.D.Luo,et.al.,Crystal structure of the NS3 protease-helicase from dengue virus. J.Virol. 2008; 82: 173-183.
15.P.Erbel,et.al, Structural basis for the activation of flaviviral NS3 protease from dengue and West Nile virus.Nat.Struct. Mol.Biol.2006;13: 372-373.
16.Robin G, Chappell K, Stoermer M J, Hu SH, Young PR, Fairlie DP, Martin J L, Structure of West Nile virus NS3 protease: ligand stabilization of the catalytic conformation. J Mol. Biol.2009;5: 1568-77.
17.Meindl P, Bodo G, Palese P, Schulman J,Tuppy H. Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid.Virology1974;58(2): 457-63.
18.Von Itzstein M, Wu WY, Kok GB, Pegg MS, Dyason JC, Jin B, Van Phan T, Smythe ML, White HF, Oliver SW,et.al: Rational design of potent sialidase- based inhibitors of influenza virus replication.Nature.1993;363(6428): 418-23.
19.Hata K, KosekiK,Yamaguchi K, Moriya S, Suzuki Y, Yingsakmongkon S, Hirai G, SodeokaM,VonItzstein M, Miyagi T: Limited inhibitory effects of oseltamivir and Zanamivir on human sialidases.Antimicrob Agents Chemother.2008;52(10): 3484-91.
20.Sugaya N, Tamura D, Yamazaki M, Ichikawa M, Kawakami C, Kawaoka Y, Mitamura K: Comparison of the clinical effectiveness of Oseltamivir and Zanamivir against influenza virus infection in children. Clin Infect Dis.2008;47(3): 339-45.
21.Karin List, Thomas H Bugge and Roman Szabo:Matriptase: Potent Proteolysis on the Cell Surface.Mol. Med.2006; 12 (1-3): 1-7.
22.Bikadi Z.,Hazai E: Application of the PM6 semi-empirical modeling proteins enhance docking accuracy of AutoDock. J. Cheminf1,2009; 15.
23.G.M.Morris, D.S.Goodsell et al. :Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of Computational Chemistry 1998;19(14): 1639-1662.
24.F.J.Solis and J.B.Wets: Minimization by Random Search Techniques. Mathematics of Operations Research1981; 6(1): 19-30.
25. Bollati M, Alvarez K, Assenberg R, Baronti C, Canard B, Cook S, et al. Structure and functionality in flavivirus NS-proteins: perspectives for drug design. Antiviral Res.2010; 87: 125–148.
26. Baronti C, Piorkowski G, Charrel RN, Boubis L, Leparc-Goffart I, de Lamballerie X. Complete coding sequence of Zika virus from a French Polynesia outbreak in 2013. Genome Announce.2014; 2: 00500– 00514.

27. Furuichi Y, Shatkin AJ. Viral and cellular mRNA capping: past and prospects. Adv Virus Res. 2000;55: 135–184.

28. Egloff MP, Benarroch D, Selisko B, Romette JL, Canard B. An RNA cap (nucleoside-2'-O-)-methyltransferase in the flavivirus RNA polymerase NS5: crystal structure and functional characterization. EMBO J. 2002;21: 2757–2768.

29. Ray D, Shah A, Tilgner M, Guo Y, Zhao Y, Dong H, et al. West Nile virus 5'-cap structure is formed by sequential guanine N-7 and ribose 2'-O methylations by nonstructural protein 5. J Virol.2006; 80: 8362–8370.

30. Potapova UV, Feranchuk SI, Potapov VV, Kulakova NV, Kondratov IG, Leonova GN, Belikov SI NS2B/NS3 protease: allosteric effect of mutations associated with the pathogenicity of tick-borneencephalitis virus. J.Biomol. Struct. Dyn.2012;30: 638-51.

31. Shiryaev SA, Cheltsov AV, Gawlik K, Ratnikov BI, Strongin AY. Virtual ligand screening of the National Cancer Institute (NCI) compound library leads to the allosteric inhibitory scaffolds of the West Nile Virus NS3 proteinase. Assay Drug Dev Technol.2011;9: 69-78.

32.MortenKallberg, Haipeng Wang, Sheng Wang, JianPeng, Zhiyong Wang, Hui Lu and JinboXu: Template based protein structure modeling using the RaptorX web server. Nature protocols2012; 7: 1511-1522.
Statistics
307 Views | 423 Downloads
Citatons
How to Cite
Singh, K. V., R. Merugu, and J. S. Solanki. “ZIKA VIRUS SERENE PROTEASE COMPLEX (NS2B-NS3) INHIBITION BY 2-AMINO-5-{[(1Z)-AMINO({[(Z)-BENZOYL]IMINO})METHYL]AMINO}-N-(5-AMINO-7-{[CARBAMOYL(PHENYL)METHYL]AMINO}-6-OXOHEPTYL)PENTANAMIDE, IN SILICO STUDIES”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 10, no. 5, May 2017, pp. 210-3, doi:10.22159/ajpcr.2017.v10i5.17286.
Section
Original Article(s)