Skip to main content

Advertisement

SpringerLink
Log in

A review on structural genomics approach applied for drug discovery against three vector-borne viral diseases: Dengue, Chikungunya and Zika

  • Review Paper
  • Published:
Virus Genes Aims and scope Submit manuscript

Abstract

Structural genomics involves the advent of three-dimensional structures of the genome encoded proteins through various techniques available. Numerous structural genomics research groups have been developed across the globe and they contribute enormously to the identification of three-dimensional structures of various proteins. In this review, we have discussed the applications of the structural genomics approach towards the discovery of potential lead-like molecules against the genomic drug targets of three vector-borne diseases, namely, Dengue, Chikungunya and Zika. Currently, all these three diseases are associated with the most important global public health problems and significant economic burden in tropical countries. Structural genomics has accelerated the identification of novel drug targets and inhibitors for the treatment of these diseases. We start with the current development status of the drug targets and antiviral drugs against these three diseases and conclude by describing challenges that need to be addressed to overcome the shortcomings in the process of drug discovery.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  1. Weigelt J, McBroom-Cerajewski LD, Schapira M, Zhao Y, Arrowmsmith CH (2008) Structural genomics and drug discovery: all in the family. Curr Opin Chem Biol 12(1):32–39

    Article  CAS  PubMed  Google Scholar 

  2. Stevens RC, Yokoyama S, Wilson IA (2001) Global efforts in structural genomics. Science 294(5540):89–92

    Article  CAS  PubMed  Google Scholar 

  3. Lundstrom K (2006) Structural genomics for membrane proteins. Cell Mol Life Sci 63(22):2597–2607

    Article  CAS  PubMed  Google Scholar 

  4. Lundstrom K (2005) Structural genomics of GPCRs. Trends Biotechnol 23(2):103–108

    Article  CAS  PubMed  Google Scholar 

  5. Marsden BD, Knapp S (2008) Doing more than just the structure—structural genomics in kinase drug discovery. Curr Opin Chem Biol 12(1):40–45

    Article  CAS  PubMed  Google Scholar 

  6. https://www.who.int/news-room/fact-sheets/detail/vector-borne-diseases

  7. Zanotto PM, Leite LC (2018) The challenges imposed by Dengue, Zika, and Chikungunya to Brazil. Front Immunol. https://doi.org/10.3389/fimmu.2018.01964

    Article  PubMed  PubMed Central  Google Scholar 

  8. Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ, Hunsperger E, Kroeger A, Margolis HS, Martínez E, Nathan MB (2010) Dengue: a continuing global threat. Nat Rev Microbiol 8(12):S7-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Modis Y, Ogata S, Clements D, Harrison SC (2003) A ligand-binding pocket in the dengue virus envelope glycoprotein. Proc Natl Acad Sci 100(12):6986–6991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xia H, Xie X, Zou J, Noble CG, Russell WK, Holthauzen LM, Choi KH, White MA, Shi PY (2020) A cocrystal structure of dengue capsid protein in complex of inhibitor. Proc Natl Acad Sci 117(30):17992–18001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li L, Lok SM, Yu IM, Zhang Y, Kuhn RJ, Chen J, Rossmann MG (2008) The flavivirus precursor membrane-envelope protein complex: structure and maturation. Science 319(5871):1830–1834

    Article  CAS  PubMed  Google Scholar 

  12. Byrd CM, Dai D, Grosenbach DW, Berhanu A, Jones KF, Cardwell KB, Schneider C, Wineinger KA, Page JM, Harver C, Stavale E (2013) A novel inhibitor of dengue virus replication that targets the capsid protein. Antimicrob Agents Chemother 57(1):15–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Smith JL, Sheridan K, Parkins CJ, Frueh L, Jemison AL, Strode K, Dow G, Nilsen A, Hirsch AJ (2018) Characterization and structure-activity relationship analysis of a class of antiviral compounds that directly bind dengue virus capsid protein and are incorporated into virions. Antiviral Res 155:12–19

    Article  CAS  PubMed  Google Scholar 

  14. Schmidt AG, Lee K, Yang PL, Harrison SC (2012) Small-molecule inhibitors of dengue-virus entry. PLoS Pathog 8(4):e1002627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yang JM, Chen YF, Tu YY, Yen KR, Yang YL (2007) Combinatorial computational approaches to identify tetracycline derivatives as flavivirus inhibitors. PLoS ONE 2(5):e428

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Poh MK, Yip A, Zhang S, Priestle JP, Ma NL, Smit JM, Wilschut J, Shi PY, Wenk MR, Schul W (2009) A small molecule fusion inhibitor of dengue virus. Antiviral Res 84(3):260–266

    Article  CAS  PubMed  Google Scholar 

  17. Leal ES, Adler NS, Fernández GA, Gebhard LG, Battini L, Aucar MG, Videla M, Monge ME, de Los Ríos AH, Dávila JA, Morell ML (2019) De novo design approaches targeting an envelope protein pocket to identify small molecules against dengue virus. Eur J Med Chem 182:111628

    Article  CAS  PubMed  Google Scholar 

  18. Zhou Z, Khaliq M, Suk JE, Patkar C, Li L, Kuhn RJ, Post CB (2008) Antiviral compounds discovered by virtual screening of small-molecule libraries against dengue virus E protein. ACS Chem Biol 3(12):765–775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kato D, Era S, Watanabe I, Arihara M, Sugiura N, Kimata K, Suzuki Y, Morita K, Hidari KI, Suzuki T (2010) Antiviral activity of chondroitin sulphate E targeting dengue virus envelope protein. Antiviral Res 88(2):236–243

    Article  CAS  PubMed  Google Scholar 

  20. Lin YL, Lei HY, Lin YS, Yeh TM, Chen SH, Liu HS (2002) Heparin inhibits dengue-2 virus infection of five human liver cell lines. Antiviral Res 56(1):93–96

    Article  CAS  PubMed  Google Scholar 

  21. Hidari KI, Takahashi N, Arihara M, Nagaoka M, Morita K, Suzuki T (2008) Structure and anti-dengue virus activity of sulfated polysaccharide from a marine alga. Biochem Biophys Res Commun 376(1):91–95

    Article  CAS  PubMed  Google Scholar 

  22. Talarico LB, Damonte EB (2007) Interference in dengue virus adsorption and uncoating by carrageenans. Virology 363(2):473–485

    Article  CAS  PubMed  Google Scholar 

  23. Lee E, Pavy M, Young N, Freeman C, Lobigs M (2006) Antiviral effect of the heparan sulfate mimetic, PI-88, against dengue and encephalitic flaviviruses. Antiviral Res 69(1):31–38

    Article  CAS  PubMed  Google Scholar 

  24. Lin LT, Chen TY, Lin SC, Chung CY, Lin TC, Wang GH, Anderson R, Lin CC, Richardson CD (2013) Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry. BMC Microbiol 13(1):1–5

    Article  CAS  Google Scholar 

  25. Faustino AF, Guerra GM, Huber RG, Hollmann A, Domingues MM, Barbosa GM, Enguita FJ, Bond PJ, Castanho MA, Da Poian AT, Almeida FC (2015) Understanding dengue virus capsid protein disordered N-terminus and pep14-23-based inhibition. ACS Chem Biol 10(2):517–526

    Article  CAS  PubMed  Google Scholar 

  26. Balinsky CA, Schmeisser H, Ganesan S, Singh K, Pierson TC, Zoon KC (2013) Nucleolin interacts with the dengue virus capsid protein and plays a role in formation of infectious virus particles. J Virol 87(24):13094–13106

    Article  PubMed  PubMed Central  Google Scholar 

  27. Qin CF, Qin ED (2004) Development of cell lines stably expressing staphylococcal nuclease fused to dengue 2 virus capsid protein for CTVI. Acta Biochim Biophys Sin 36(8):577–582

    Article  CAS  PubMed  Google Scholar 

  28. Schmidt AG, Yang PL, Harrison SC (2010) Peptide inhibitors of dengue-virus entry target a late-stage fusion intermediate. PLoS Pathog 6(4):e1000851

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Hrobowski YM, Garry RF, Michael SF (2005) Peptide inhibitors of dengue virus and West Nile virus infectivity. Virology J 2(1):1

    Article  CAS  Google Scholar 

  30. Isa DM, Chin SP, Chong WL, Zain SM, Abd Rahman N, Lee VS (2019) Dynamics and binding interactions of peptide inhibitors of dengue virus entry. J Biol Phys 45(1):63–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Costin JM, Jenwitheesuk E, Lok SM, Hunsperger E, Conrads KA, Fontaine KA, Rees CR, Rossmann MG, Isern S, Samudrala R, Michael SF (2010) Structural optimization and de novo design of dengue virus entry inhibitory peptides. PLoS Negl Trop Dis 4(6):e721

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Panya A, Sawasdee N, Junking M, Srisawat C, Choowongkomon K, Yenchitsomanus PT (2015) A peptide inhibitor derived from the conserved ectodomain region of DENV membrane (M) protein with activity against dengue virus infection. Chem Biol Drug Des 86(5):1093–1104

    Article  CAS  PubMed  Google Scholar 

  33. Edeling MA, Diamond MS, Fremont DH (2014) Structural basis of Flavivirus NS1 assembly and antibody recognition. Proc Natl Acad Sci 111(11):4285–4290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Libraty DH, Young PR, Pickering D, Endy TP, Kalayanarooj S, Green S et al (2002) High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis 186(8):1165–1168. https://doi.org/10.1086/343813

    Article  CAS  PubMed  Google Scholar 

  35. Songprakhon P, Thaingtamtanha T, Limjindaporn T, Puttikhunt C, Srisawat C, Luangaram P, Dechtawewat T, Uthaipibull C, Thongsima S, Yenchitsomanus PT, Malasit P (2020) Peptides targeting dengue viral nonstructural protein 1 inhibit dengue virus production. Sci Rep 10(1):1–6

    Article  CAS  Google Scholar 

  36. Chandramouli S, Joseph JS, Daudenarde S, Gatchalian J, Cornillez-Ty C, Kuhn P (2010) Serotype-specific structural differences in the protease-cofactor complexes of the dengue virus family. J Virol 84(6):3059–3067

    Article  CAS  PubMed  Google Scholar 

  37. Rothan HA, Han HC, Ramasamy TS, Othman S, Abd Rahman N, Yusof R (2012) Inhibition of dengue NS2B-NS3 protease and viral replication in Vero cells by recombinant retrocyclin-1. BMC Infect Dis 12(1):1–9

    Article  CAS  Google Scholar 

  38. Yang CC, Hu HS, Wu RH, Wu SH, Lee SJ, Jiaang WT, Chern JH, Huang ZS, Wu HN, Chang CM, Yueh A (2014) A novel dengue virus inhibitor, BP13944, discovered by high-throughput screening with dengue virus replicon cells selects for resistance in the viral NS2B/NS3 protease. Antimicrob Agents Chemother 58(1):110–119

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Tomlinson SM, Malmstrom RD, Russo A, Mueller N, Pang YP, Watowich SJ (2009) Structure-based discovery of dengue virus protease inhibitors. Antiviral Res 82(3):110–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Matusan AE, Pryor MJ, Davidson AD, Wright PJ (2001) Mutagenesis of the Dengue virus type 2 NS3 protein within and outside helicase motifs: effects on enzyme activity and virus replication. J Virol 75(20):9633–9643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Swarbrick CM, Basavannacharya C, Chan KW, Chan SA, Singh D, Wei N, Phoo WW, Luo D, Lescar J, Vasudevan SG (2017) NS3 helicase from dengue virus specifically recognizes viral RNA sequence to ensure optimal replication. Nucleic Acids Res 45(22):12904–12920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mastrangelo E, Pezzullo M, De Burghgraeve T, Kaptein S, Pastorino B, Dallmeier K, de Lamballerie X, Neyts J, Hanson AM, Frick DN, Bolognesi M (2012) Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J Antimicrob Chemother 67(8):1884–1894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Byrd CM, Grosenbach DW, Berhanu A, Dai D, Jones KF, Cardwell KB, Schneider C, Yang G, Tyavanagimatt S, Harver C, Wineinger KA (2013) Novel benzoxazole inhibitor of dengue virus replication that targets the NS3 helicase. Antimicrob Agents Chemother 57(4):1902–1912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Basavannacharya C, Vasudevan SG (2014) Suramin inhibits helicase activity of NS3 protein of dengue virus in a fluorescence-based high throughput assay format. Biochem Biophys Res Commun 453(3):539–544

    Article  CAS  PubMed  Google Scholar 

  45. Norazharuddin H, Lai NS (2018) Roles and prospects of dengue virus non-structural proteins as antiviral targets: an easy digest. Malays J Med Sci 25(5):6

    PubMed  PubMed Central  Google Scholar 

  46. van Cleef KW, Overheul GJ, Thomassen MC, Marjakangas JM, van Rij RP (2016) Escape mutations in NS4B render dengue virus insensitive to the antiviral activity of the paracetamol metabolite AM404. Antimicrob Agents Chemother 60(4):2554–2557

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Xie X, Wang QY, Xu HY, Qing M, Kramer L, Yuan Z, Shi PY (2011) Inhibition of dengue virus by targeting viral NS4B protein. J Virol 85(21):11183–11195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nguyen NM, Tran CN, Phung LK, Duong KT, Huynh HL, Farrar J, Nguyen QT, Tran HT, Nguyen CV, Merson L, Hoang LT (2013) A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients. J Infect Dis 207(9):1442–1450

    Article  CAS  PubMed  Google Scholar 

  49. Carocci M, Hinshaw SM, Rodgers MA, Villareal VA, Burri DJ, Pilankatta R, Maharaj NP, Gack MU, Stavale EJ, Warfield KL, Yang PL (2015) The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication. Antimicrob Agents Chemother 59(1):85–95

    Article  PubMed  CAS  Google Scholar 

  50. Yokokawa F, Nilar S, Noble CG, Lim SP, Rao R, Tania S, Wang G, Lee G, Hunziker J, Karuna R, Manjunatha U (2016) Discovery of potent non-nucleoside inhibitors of dengue viral RNA-dependent RNA polymerase from a fragment hit using structure-based drug design. J Med Chem 59(8):3935–3952

    Article  CAS  PubMed  Google Scholar 

  51. Lim SP, Noble CG, Nilar S, Shi PY, Yokokawa F (2018) Discovery of potent non-nucleoside inhibitors of dengue viral RNA-dependent RNA polymerase from fragment screening and structure-guided design. Dengue Zika: Control Antivir Treat Strateg. https://doi.org/10.1007/978-981-10-8727-1_14

    Article  Google Scholar 

  52. Benmansour F, Trist I, Coutard B, Decroly E, Querat G, Brancale A, Barral K (2017) Discovery of novel dengue virus NS5 methyltransferase non-nucleoside inhibitors by fragment-based drug design. Eur J Med Chem 125:865–880

    Article  CAS  PubMed  Google Scholar 

  53. Haese N, Powers J, Streblow DN (2020) Small molecule inhibitors targeting chikungunya virus. Chikungunya Virus. https://doi.org/10.1007/82_2020_195

    Article  Google Scholar 

  54. Sharma R, Fatma B, Saha A, Bajpai S, Sistla S, Dash PK, Parida M, Kumar P, Tomar S (2016) Inhibition of chikungunya virus by picolinate that targets viral capsid protein. Virology 498:265–276

    Article  CAS  PubMed  Google Scholar 

  55. Kumar R, Nehul S, Singh A, Tomar S (2021) Identification and evaluation of antiviral potential of thymoquinone, a natural compound targeting Chikungunya virus capsid protein. Virology 561:36–46

    Article  CAS  PubMed  Google Scholar 

  56. Sharma R, Kesari P, Kumar P, Tomar S (2018) Structure-function insights into chikungunya virus capsid protein: small molecules targeting capsid hydrophobic pocket. Virology 515:223–234

    Article  CAS  PubMed  Google Scholar 

  57. Fatma B, Kumar R, Singh VA, Nehul S, Sharma R, Kesari P, Kuhn RJ, Tomar S (2020) Alphavirus capsid protease inhibitors as potential antiviral agents for Chikungunya infection. Antiviral Res 179:104808

    Article  CAS  PubMed  Google Scholar 

  58. Weber C, Berberich E, von Rhein C, Henß L, Hildt E, Schnierle BS (2017) Identification of functional determinants in the chikungunya virus E2 protein. PLoS Negl Trop Dis 11(1):e0005318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Uchime O, Fields W, Kielian M (2013) The role of E3 in pH protection during alphavirus assembly and exit. J Virol 87(18):10255–10262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Voss JE, Vaney MC, Duquerroy S, Vonrhein C, Girard-Blanc C, Crublet E, Thompson A, Bricogne G, Rey FA (2010) Glycoprotein organization of Chikungunya virus particles revealed by X-ray crystallography. Nature 468(7324):709–712

    Article  CAS  PubMed  Google Scholar 

  61. Nguyen PT, Yu H, Keller PA (2018) Molecular docking studies to explore potential binding pockets and inhibitors for chikungunya virus envelope glycoproteins. Interdiscip Sci: Comput Life Sci 10(3):515–524

    Article  CAS  Google Scholar 

  62. Passos GF, Gomes MG, Aquino TM, Araújo-Júnior JX, Souza SJ, Cavalcante JP, Santos EC, Bassi ÊJ, Silva-Júnior EF (2020) Computer-aided design, synthesis, and antiviral evaluation of novel acrylamides as potential inhibitors of E3-E2-E1 glycoproteins complex from Chikungunya virus. Pharmaceuticals 13(7):141

    Article  CAS  PubMed Central  Google Scholar 

  63. Islamuddin M, Afzal O, Khan WH, Hisamuddin M, Altamimi AS, Husain I, Kato K, Alamri MA, Parveen S (2021) Inhibition of Chikungunya Virus Infection by 4-Hydroxy-1-Methyl-3-(3-morpholinopropanoyl) quinoline-2 (1 H)-one (QVIR) Targeting nsP2 and E2 Proteins. ACS Omega 6(14):9791–9803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Dey D, Siddiqui SI, Mamidi P, Ghosh S, Kumar CS, Chattopadhyay S, Ghosh S, Banerjee M (2019) The effect of amantadine on an ion channel protein from Chikungunya virus. PLoS Negl Trop Dis 13(7):e0007548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Rupp JC, Sokoloski KJ, Gebhart NN, Hardy RW (2015) Alphavirus RNA synthesis and non-structural protein functions. J Gen Virol 96(Pt 9):2483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Feibelman KM, Fuller BP, Li L, LaBarbera DV, Geiss BJ (2018) Identification of small molecule inhibitors of the Chikungunya virus nsP1 RNA capping enzyme. Antivir Res 154:124–131

    Article  CAS  PubMed  Google Scholar 

  67. Gigante A, Canela MD, Delang L, Priego EM, Camarasa MJ, Querat G, Neyts J, Leyssen P, Pérez-Pérez MJ (2014) Identification of [1, 2, 3] triazolo [4, 5-d] pyrimidin-7 (6 H)-ones as novel inhibitors of Chikungunya virus replication. J Med Chem 57(10):4000–4008

    Article  CAS  PubMed  Google Scholar 

  68. Mudgal R, Mahajan S, Tomar S (2020) Inhibition of Chikungunya virus by an adenosine analog targeting the SAM-dependent nsP1 methyltransferase. FEBS Lett 594(4):678–694

    Article  CAS  PubMed  Google Scholar 

  69. Kovacikova K, Morren BM, Tas A, Albulescu IC, van Rijswijk R, Jarhad DB, Shin YS, Jang MH, Kim G, Lee HW, Jeong LS (2020) 6′-β-Fluoro-homoaristeromycin and 6′-fluoro-homoneplanocin A are potent inhibitors of chikungunya virus replication through their direct effect on viral nonstructural protein 1. Antimicrob Agents Chemother 64(4):e02532-e2619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Moesslacher J, Battisti V, Delang L, Neyts J, Abdelnabi R, Pürstinger G, Urban E, Langer T (2020) Identification of 2-(4-(phenylsulfonyl) piperazine-1-yl) pyrimidine analogues as novel inhibitors of chikungunya virus. ACS Med Chem Lett 11(5):906–912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang K, Law YS, Law MC, Tan YB, Wirawan M, Luo D (2021) Structural insights into viral RNA capping and plasma membrane targeting by Chikungunya virus nonstructural protein 1. Cell Host Microbe 29(5):757–764

    Article  CAS  PubMed  Google Scholar 

  72. Kovacikova K, Gorostiola González M, Jones R, Reguera J, Gigante A, Pérez-Pérez MJ, Pürstinger G, Moesslacher J, Langer T, Jeong LS, Delang L (2021) Structural insights into the mechanisms of action of functionally distinct classes of Chikungunya virus nonstructural protein 1 inhibitors. Antimicrob Agents Chemother 65(7):e02566-e2620

    Article  CAS  PubMed Central  Google Scholar 

  73. Fros JJ, van der Maten E, Vlak JM, Pijlman GP (2013) The C-terminal domain of chikungunya virus nsP2 independently governs viral RNA replication, cytopathicity, and inhibition of interferon signaling. J Virol 87(18):10394–10400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Narwal M, Singh H, Pratap S, Malik A, Kuhn RJ, Kumar P, Tomar S (2018) Crystal structure of chikungunya virus nsP2 cysteine protease reveals a putative flexible loop blocking its active site. Int J Biol Macromol 116:451–462

    Article  CAS  PubMed  Google Scholar 

  75. Bassetto M, De Burghgraeve T, Delang L, Massarotti A, Coluccia A, Zonta N, Gatti V, Colombano G, Sorba G, Silvestri R, Tron GC (2013) Computer-aided identification, design and synthesis of a novel series of compounds with selective antiviral activity against chikungunya virus. Antivir Res 98(1):12–18

    Article  CAS  PubMed  Google Scholar 

  76. Nguyen PT, Yu H, Keller PA (2015) Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches. J Mol Graph Model 57:1–8

    Article  CAS  PubMed  Google Scholar 

  77. Agarwal T, Asthana S, Bissoyi A (2015) Molecular modeling and docking study to elucidate novel chikungunya virus nsP2 protease inhibitors. Indian J Pharm Sci 77(4):453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jain J, Kumari A, Somvanshi P, Grover A, Pai S, Sunil S (2017) In silico analysis of natural compounds targeting structural and nonstructural proteins of chikungunya virus. F1000Research 6:1601

    Article  PubMed  PubMed Central  Google Scholar 

  79. Kumar P, Kumar D, Giri R (2019) Targeting the nsp2 cysteine protease of chikungunya virus using FDA approved library and selected cysteine protease inhibitors. Pathogens 8(3):128

    Article  PubMed Central  CAS  Google Scholar 

  80. Meena MK, Kumar D, Kumari K, Kaushik NK, Kumar RV, Bahadur I, Vodwal L, Singh P (2021) Promising inhibitors of nsp2 of CHIKV using molecular docking and temperature-dependent molecular dynamics simulations. J Biomol Struct Dyn. https://doi.org/10.1080/07391102.2021.1873863

    Article  PubMed  Google Scholar 

  81. Rasool N, Bakht A, Hussain W (2021) Analysis of inhibitor binding combined with reactivity studies to discover the potentially inhibiting phytochemicals targeting Chikungunya viral replication. Curr Drug Discov Technol 18(3):437–450

    Article  CAS  PubMed  Google Scholar 

  82. Lani R, Agharbaoui FE, Hassandarvish P, Teoh BT, Sam SS, Zandi K, Rahman NA, AbuBakar S (2021) In silico studies of fisetin and silymarin as novel chikungunya virus nonstructural proteins inhibitors. Future Virol 16(3):167–180

    Article  CAS  Google Scholar 

  83. Singh Jadav S, Nayan Sinha B, Pastorino B, de Lamballerie X, Hilgenfeld R, Jayaprakash V (2015) Identification of pyrazole derivative as an antiviral agent against Chikungunya through HTVS. Lett Drug Des Discov 12(4):292–301

    Article  CAS  Google Scholar 

  84. Das PK, Puusepp L, Varghese FS, Utt A, Ahola T, Kananovich DG, Lopp M, Merits A, Karelson M (2016) Design and validation of novel chikungunya virus protease inhibitors. Antimicrob Agents Chemother 60(12):7382–7395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ivanova L, Rausalu K, Žusinaite E, Tammiku-Taul J, Merits A, Karelson M (2021) 1, 3-Thiazolbenzamide derivatives as Chikungunya virus nsP2 protease inhibitors. ACS Omega 6(8):5786–5794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Eberle RJ, Olivier DS, Pacca CC, Avilla CM, Nogueira ML, Amaral MS, Willbold D, Arni RK, Coronado MA (2021) In vitro study of Hesperetin and Hesperidin as inhibitors of zika and chikungunya virus proteases. PLoS ONE 16(3):e0246319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tripathi PK, Soni A, Yadav SP, Kumar A, Gaurav N, Raghavendhar S, Sharma P, Sunil S, Jayaram B, Patel AK (2020) Evaluation of novobiocin and telmisartan for anti-CHIKV activity. Virology 548:250–260

    Article  CAS  PubMed  Google Scholar 

  88. Tripathi PK, Singh J, Gaurav N, Garg DK, Patel AK (2020) In-silico and biophysical investigation of biomolecular interaction between naringin and nsP2 of the chikungunya virus. Int J Biol Macromol 160:1061–1065

    Article  CAS  PubMed  Google Scholar 

  89. Singh H, Mudgal R, Narwal M, Kaur R, Singh VA, Malik A, Chaudhary M, Tomar S (2018) Chikungunya virus inhibition by peptidomimetic inhibitors targeting virus-specific cysteine protease. Biochimie 149:51–61

    Article  CAS  PubMed  Google Scholar 

  90. El-labbad EM, Ismail MA, Abou Ei Ella DA, Ahmed M, Wang F, Barakat KH, Abouzid KA (2015) Discovery of novel peptidomimetics as irreversible CHIKV Ns P 2 protease inhibitors using quantum mechanical-based ligand descriptors. Chem Biol Drug Des 86(6):1518–1527

    Article  CAS  PubMed  Google Scholar 

  91. Law YS, Utt A, Tan YB, Zheng J, Wang S, Chen MW, Griffin PR, Merits A, Luo D (2019) Structural insights into RNA recognition by the Chikungunya virus nsP2 helicase. Proc Natl Acad Sci 116(19):9558–9567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Abraham R, Hauer D, McPherson RL, Utt A, Kirby IT, Cohen MS, Merits A, Leung AK, Griffin DE (2018) ADP-ribosyl–binding and hydrolase activities of the alphavirus nsP3 macrodomain are critical for initiation of virus replication. Proc Natl Acad Sci 115(44):E10457–E10466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Malet H, Coutard B, Jamal S, Dutartre H, Papageorgiou N, Neuvonen M, Ahola T, Forrester N, Gould EA, Lafitte D, Ferron F (2009) The crystal structures of Chikungunya and Venezuelan equine encephalitis virus nsP3 macro domains define a conserved adenosine binding pocket. J Virol 83(13):6534–6545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhang S, Garzan A, Haese N, Bostwick R, Martinez-Gzegozewska Y, Rasmussen L, Streblow DN, Haise MT, Pathak AK, Augelli-Szafran CE, Wu M (2021) Pyrimidone inhibitors targeting Chikungunya Virus nsP3 macrodomain by fragment-based drug design. PLoS ONE 16(1):e0245013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Shimizu JF, Martins DO, McPhillie MJ, Roberts GC, Zothner C, Merits A, Harris M, Jardim AC (2020) Is the ADP ribose site of the Chikungunya virus NSP3 Macro domain a target for antiviral approaches? Acta Trop 207:105490

    Article  CAS  PubMed  Google Scholar 

  96. Nguyen PT, Yu H, Keller PA (2014) Discovery of in silico hits targeting the nsP3 macro domain of chikungunya virus. J Mol Model 20(5):1–2

    Article  CAS  Google Scholar 

  97. Kumar D, Kumari K, Jayaraj A, Singh P (2020) Development of a theoretical model for the inhibition of nsP3 protease of Chikungunya virus using pyranooxazoles. J Biomol Struct Dyn 38(10):3018–3034

    Article  CAS  PubMed  Google Scholar 

  98. Meena MK, Kumar D, Jayaraj A, Kumar A, Kumari K, Katata-Seru LM, Bahadur I, Kumar V, Sherawat A, Singh P (2020) Designed thiazolidines: an arsenal for the inhibition of nsP3 of CHIKV using molecular docking and MD simulations. J Biomol Struct Dyn. https://doi.org/10.1080/07391102.2020.1832918

    Article  PubMed  Google Scholar 

  99. Kumar D, Meena MK, Kumari K, Patel R, Jayaraj A, Singh P (2020) In-silico prediction of novel drug-target complex of nsp3 of CHIKV through molecular dynamic simulation. Heliyon 6(8):e04720

    Article  PubMed  PubMed Central  Google Scholar 

  100. Chaudhary M, Sehgal D (2021) In silico identification of natural antiviral compounds as a potential inhibitor of chikungunya virus non-structural protein 3 macrodomain. J Biomol Struct Dyn. https://doi.org/10.1080/07391102.2021.1960195

    Article  PubMed  PubMed Central  Google Scholar 

  101. Patil P, Agrawal M, Almelkar S, Jeengar MK, More A, Alagarasu K, Kumar NV, Mainkar PS, Parashar D, Cherian S (2021) In vitro and in vivo studies reveal α-Mangostin, a xanthonoid from Garcinia mangostana, as a promising natural antiviral compound against chikungunya virus. Virol J 18(1):1–2

    Article  CAS  Google Scholar 

  102. LaStarza MW, Lemm JA, Rice CM (1994) Genetic analysis of the nsP3 region of Sindbis virus: evidence for roles in minus-strand and subgenomic RNA synthesis. J Virol 68(9):5781–5791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nandi I, Gupta A, Chaudhary VK, Gupta V, Gabrani R, Gupta S (2019) Expression, purification and functional characterization of recombinant hypervariable region (HVR) of Chikungunya virus nsP3 protein. 3 Biotech 9(6):1–8

    Article  Google Scholar 

  104. Satheesh G, Prabhu PN, Venkataramana M (2014) 3D Modeling of dengue virus NS4B and Chikungunya virus nsP4: identification of a common drug target and designing a single antiviral inhibitor. Curr Comput Aided Drug Des 10(4):361–373

    Article  CAS  PubMed  Google Scholar 

  105. Reyes-Gastellou A, Jiménez-Alberto A, Castelán-Vega JA, Aparicio-Ozores G, Ribas-Aparicio RM (2021) Chikungunya nsP4 homology modeling reveals a common motif with Zika and Dengue RNA polymerases as a potential therapeutic target. J Mol Model 27(9):1–2

    Article  CAS  Google Scholar 

  106. Wada Y, Orba Y, Sasaki M, Kobayashi S, Carr MJ, Nobori H, Sato A, Hall WW, Sawa H (2017) Discovery of a novel antiviral agent targeting the nonstructural protein 4 (nsP4) of chikungunya virus. Virology 505:102–112

    Article  CAS  PubMed  Google Scholar 

  107. Ehteshami M, Tao S, Zandi K, Hsiao HM, Jiang Y, Hammond E, Amblard F, Russell OO, Merits A, Schinazi RF (2017) Characterization of β-d-N 4-hydroxycytidine as a novel inhibitor of chikungunya virus. Antimicrob Agents Chemother 61(4):e02395-e2416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ferreira AC, Reis PA, de Freitas CS, Sacramento CQ, Villas Bôas Hoelz L, Bastos MM, Mattos M, Rocha N, Gomes de Azevedo Quintanilha I, da Silva Gouveia Pedrosa C, Rocha Quintino Souza L (2019) Beyond members of the Flaviviridae family, sofosbuvir also inhibits chikungunya virus replication. Antimicrob Agents Chemother 63(2):e01389-18

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kumar SP, Kapopara RG, Patni MI, Pandya HA, Jasrai YT, Patel SK (2012) Exploring the polymerase activity of chikungunya viral non structural protein 4 (nsP4) using molecular modeling, epharmacophore and docking studies. Int J Pharm Life Sci 3(6):1752–1765

    Google Scholar 

  110. Ghildiyal R, Gupta S, Gabrani R, Joshi G, Gupta A, Chaudhary VK, Gupta V (2019) In silico study of chikungunya polymerase, a potential target for inhibitors. Virusdisease 30(3):394–402

    Article  PubMed  PubMed Central  Google Scholar 

  111. Ayres CF, Guedes DR, Paiva MH, Morais-Sobral MC, Krokovsky L, Machado LC, Melo-Santos MA, Crespo M, Oliveira CM, Ribeiro RS, Cardoso OA (2019) Zika virus detection, isolation and genome sequencing through Culicidae sampling during the epidemic in Vitória, Espírito Santo, Brazil. Parasit Vectors 12(1):220

    Article  PubMed  PubMed Central  Google Scholar 

  112. Shang Z, Song H, Shi Y, Qi J, Gao GF (2018) Crystal structure of the capsid protein from Zika virus. J Mol Biol 430(7):948–962

    Article  CAS  PubMed  Google Scholar 

  113. Ahmed SR, Banik A, Anni SM, Chowdhury MM (2020) Plant derived bioactive compounds as potential inhibitors of ZIKA virus: an in silico investigation. bioRxiv. https://doi.org/10.1101/2020.11.11.378083

    Article  PubMed  PubMed Central  Google Scholar 

  114. Dai L, Song J, Lu X, Deng YQ, Musyoki AM, Cheng H, Zhang Y, Yuan Y, Song H, Haywood J, Xiao H (2016) Structures of the Zika virus envelope protein and its complex with a flavivirus broadly protective antibody. Cell Host Microbe 19(5):696–704

    Article  CAS  PubMed  Google Scholar 

  115. Fernando S, Fernando T, Stefanik M, Eyer L, Ruzek D (2016) An approach for Zika virus inhibition using homology structure of the envelope protein. Mol Biotechnol 58(12):801–806

    Article  CAS  PubMed  Google Scholar 

  116. Carneiro BM, Batista MN, Braga AC, Nogueira ML, Rahal P (2016) The green tea molecule EGCG inhibits Zika virus entry. Virology 496:215–218

    Article  CAS  PubMed  Google Scholar 

  117. Barrows NJ, Campos RK, Powell ST, Prasanth KR, Schott-Lerner G, Soto-Acosta R, Galarza-Muñoz G, McGrath EL, Urrabaz-Garza R, Gao J, Wu P (2016) A screen of FDA-approved drugs for inhibitors of Zika virus infection. Cell Host Microbe 20(2):259–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mounce BC, Cesaro T, Carrau L, Vallet T, Vignuzzi M (2017) Curcumin inhibits Zika and chikungunya virus infection by inhibiting cell binding. Antivir Res 142:148–157

    Article  CAS  PubMed  Google Scholar 

  119. Rausch K, Hackett BA, Weinbren NL, Reeder SM, Sadovsky Y, Hunter CA, Schultz DC, Coyne CB, Cherry S (2017) Screening bioactives reveals nanchangmycin as a broad spectrum antiviral active against Zika virus. Cell Rep 18(3):804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Röcker AE, Müller JA, Dietzel E, Harms M, Krüger F, Heid C, Sowislok A, Riber CF, Kupke A, Lippold S, von Einem J (2018) The molecular tweezer CLR01 inhibits Ebola and Zika virus infection. Antiviral Res 152:26–35

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Oo A, Teoh BT, Sam SS, Bakar SA, Zandi K (2019) Baicalein and baicalin as Zika virus inhibitors. Adv Virol 164(2):585–593

    CAS  Google Scholar 

  122. Gao Y, Tai W, Wang N, Li X, Jiang S, Debnath AK, Du L, Chen S (2019) Identification of novel natural products as effective and broad-spectrum anti-Zika virus inhibitors. Viruses 11(11):1019

    Article  CAS  PubMed Central  Google Scholar 

  123. Telehany SM, Humby MS, McGee TD Jr, Riley SP, Jacobs A, Rizzo RC (2020) Identification of Zika virus inhibitors using homology modeling and similarity-based screening to target glycoprotein E. Biochemistry 59(39):3709–3724

    Article  CAS  PubMed  Google Scholar 

  124. Pitts J, Hsia CY, Lian W, Wang J, Pfeil MP, Kwiatkowski N, Li Z, Jang J, Gray NS, Yang PL (2019) Identification of small molecule inhibitors targeting the Zika virus envelope protein. Antivir Res 164:147–153

    Article  CAS  PubMed  Google Scholar 

  125. Sharma N, Prosser O, Kumar P, Tuplin A, Giri R (2020) Small molecule inhibitors possibly targeting the rearrangement of Zika virus envelope protein. Antivir Res 182:104876

    Article  CAS  PubMed  Google Scholar 

  126. Zou M, Liu H, Li J, Yao X, Chen Y, Ke C, Liu S (2020) Structure-activity relationship of flavonoid bifunctional inhibitors against Zika virus infection. Biochem Pharmacol 177:113962

    Article  CAS  PubMed  Google Scholar 

  127. Yu Y, Deng YQ, Zou P, Wang Q, Dai Y, Yu F, Du L, Zhang NN, Tian M, Hao JN, Meng Y (2017) A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses. Nat Commun 8(1):1–2

    Article  CAS  Google Scholar 

  128. Chen L, Liu Y, Wang S, Sun J, Wang P, Xin Q, Zhang L, Xiao G, Wang W (2017) Antiviral activity of peptide inhibitors derived from the protein E stem against Japanese encephalitis and Zika viruses. Antivir Res 141:140–149

    Article  CAS  PubMed  Google Scholar 

  129. Wang D, Chen C, Liu S, Zhou H, Yang K, Zhao Q, Ji X, Chen C, Xie W, Wang Z, Mi LZ (2017) A mutation identified in neonatal microcephaly destabilizes Zika virus NS1 assembly in vitro. Sci Rep 7(1):1

    PubMed  PubMed Central  CAS  Google Scholar 

  130. Raza S, Abbas G, Azam SS (2019) Screening pipeline for Flavivirus based inhibitors for Zika virus NS1. IEEE/ACM Trans Comput Biol Bioinform 17(5):1751–1761

    Article  PubMed  Google Scholar 

  131. Ahmad N, Badshah SL, Junaid M, Ur Rehman A, Muhammad A, Khan K (2021) Structural insights into the Zika virus NS1 protein inhibition using a computational approach. J Biomol Struct Dyn 39(8):3004–3011

    Article  CAS  PubMed  Google Scholar 

  132. Erbel P, Schiering N, D’Arcy A, Renatus M, Kroemer M, Lim SP, Yin Z, Keller TH, Vasudevan SG, Hommel U (2006) Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus. Nat Struct Mol Biol 13(4):372–373

    Article  CAS  PubMed  Google Scholar 

  133. Lei J, Hansen G, Nitsche C, Klein CD, Zhang L, Hilgenfeld R (2016) Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor. Science 353(6298):503–505

    Article  CAS  PubMed  Google Scholar 

  134. Yuan S, Chan JF, den Haan H, Chik KK, Zhang AJ, Chan CC, Poon VK, Yip CC, Mak WW, Zhu Z, Zou Z (2017) Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo. Antivir Res 145:33–43

    Article  CAS  PubMed  Google Scholar 

  135. Roy A, Lim L, Srivastava S, Lu Y, Song J (2017) Solution conformations of Zika NS2B-NS3pro and its inhibition by natural products from edible plants. PLoS ONE 12(7):e0180632

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Li Z, Brecher M, Deng YQ, Zhang J, Sakamuru S, Liu B, Huang R, Koetzner CA, Allen CA, Jones SA, Chen H (2017) Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction. Cell Res 27(8):1046–1064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lee H, Ren J, Nocadello S, Rice AJ, Ojeda I, Light S, Minasov G, Vargas J, Nagarathnam D, Anderson WF, Johnson ME (2017) Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus. Antivir Res 139:49–58

    Article  CAS  PubMed  Google Scholar 

  138. Lim HJ, Nguyen TT, Kim NM, Park JS, Jang TS, Kim D (2017) Inhibitory effect of flavonoids against NS2B-NS3 protease of ZIKA virus and their structure activity relationship. Biotechnol Lett 39(3):415–421

    Article  CAS  PubMed  Google Scholar 

  139. Chan JF, Chik KK, Yuan S, Yip CC, Zhu Z, Tee KM, Tsang JO, Chan CC, Poon VK, Lu G, Zhang AJ (2017) Novel antiviral activity and mechanism of bromocriptine as a Zika virus NS2B-NS3 protease inhibitor. Antivir Res 141:29–37

    Article  CAS  PubMed  Google Scholar 

  140. Li Y, Zhang Z, Phoo WW, Loh YR, Li R, Yang HY, Jansson AE, Hill J, Keller TH, Nacro K, Luo D (2018) Structural insights into the inhibition of Zika virus NS2B-NS3 protease by a small-molecule inhibitor. Structure 26(4):555–564

    Article  CAS  PubMed  Google Scholar 

  141. Kumar A, Liang B, Aarthy M, Singh SK, Garg N, Mysorekar IU, Giri R (2018) Hydroxychloroquine inhibits Zika virus NS2B-NS3 protease. ACS Omega 3(12):18132–18141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Coronado MA, Eberle RJ, Bleffert N, Feuerstein S, Olivier DS, de Moraes FR, Willbold D, Arni RK (2018) Zika virus NS2B/NS3 proteinase: a new target for an old drug-Suramin a lead compound for NS2B/NS3 proteinase inhibition. Antivir Res 160:118–125

    Article  CAS  PubMed  Google Scholar 

  143. Li Z, Sakamuru S, Huang R, Brecher M, Koetzner CA, Zhang J, Chen H, Qin CF, Zhang QY, Zhou J, Kramer LD (2018) Erythrosin B is a potent and broad-spectrum orthosteric inhibitor of the flavivirus NS2B-NS3 protease. Antivir Res 150:217–225

    Article  CAS  PubMed  Google Scholar 

  144. Santos FR, Nunes DA, Lima WG, Davyt D, Santos LL, Taranto AG, Ferreira MSJ (2019) Identification of Zika virus NS2B-NS3 protease inhibitors by structure-based virtual screening and drug repurposing approaches. J Chem Inf Model 60(2):731–737

    Article  PubMed  CAS  Google Scholar 

  145. Yao Y, Huo T, Lin YL, Nie S, Wu F, Hua Y, Wu J, Kneubehl AR, Vogt MB, Rico-Hesse R, Song Y (2019) Discovery, X-ray crystallography and antiviral activity of allosteric inhibitors of flavivirus NS2B-NS3 protease. J Am Chem Soc 141(17):6832–6836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Rassias G, Zogali V, Swarbrick CM, Chan KW, Chan SA, Gwee CP, Wang S, Kaplanai E, Canko A, Kiousis D, Lescar J (2019) Cell-active carbazole derivatives as inhibitors of the Zika virus protease. Eur J Med Chem 180:536–545

    Article  CAS  PubMed  Google Scholar 

  147. Pathak N, Kuo YP, Chang TY, Huang CT, Hung HC, Hsu JT, Yu GY, Yang JM (2020) Zika virus NS3 protease pharmacophore anchor model and drug discovery. Sci Rep 10(1):1–7

    Article  CAS  Google Scholar 

  148. Cui X, Zhou R, Huang C, Zhang R, Wang J, Zhang Y, Ding J, Li X, Zhou J, Cen S (2020) Identification of theaflavin-3, 3’-digallate as a novel Zika virus protease inhibitor. Front Pharmacol. https://doi.org/10.3389/fphar.2020.514313

    Article  PubMed  PubMed Central  Google Scholar 

  149. Pach S, Sarter TM, Yousef R, Schaller D, Bergemann S, Arkona C, Rademann J, Nitsche C, Wolber G (2020) Catching a moving target: comparative modeling of flaviviral NS2B-NS3 reveals small molecule Zika protease inhibitors. ACS Med Chem Lett 11(4):514–520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Voss S, Nitsche C (2020) Inhibitors of the Zika virus protease NS2B-NS3. Bioorg Med Chem Lett 30(5):126965

    Article  CAS  PubMed  Google Scholar 

  151. Akaberi D, Chinthakindi PK, Båhlström A, Palanisamy N, Sandström A, Lundkvist Å, Lennerstrand J (2020) Identification of a C2-symmetric diol based human immunodeficiency virus protease inhibitor targeting Zika virus NS2B-NS3 protease. J Biomol Struct Dyn 38(18):5526–5536

    Article  CAS  PubMed  Google Scholar 

  152. Coluccia A, Puxeddu M, Nalli M, Wei CK, Wu YH, Mastrangelo E, Elamin T, Tarantino D, Bugert JJ, Schreiner B, Nolte J (2020) Discovery of Zika virus NS2B/NS3 inhibitors that prevent mice from life-threatening infection and brain damage. ACS Med Chem Lett 11(10):1869–1874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lima CS, Mottin M, de Assis LR, Mesquita NC, de Paula Sousa BK, Coimbra LD, Bispo-dos-Santos K, Zorn KM, Guido RV, Ekins S, Marques RE (2021) Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors. Bioorg Chem 109:104719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Nie S, Yao Y, Wu F, Wu X, Zhao J, Hua Y, Wu J, Huo T, Lin YL, Kneubehl AR, Vogt MB (2021) Synthesis, structure–activity relationships, and antiviral activity of allosteric inhibitors of Flavivirus NS2B–NS;3 protease. J Med Chem 64(5):2777–2800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Nie S, Zhao J, Wu X, Yao Y, Wu F, Lin YL, Li X, Kneubehl AR, Vogt MB, Rico-Hesse R, Song Y (2021) Synthesis, structure-activity relationship and antiviral activity of indole-containing inhibitors of Flavivirus NS2B-NS3 protease. Eur J Med Chem 225:113767

    Article  CAS  PubMed  Google Scholar 

  156. Chong Teoh T, Al-Harbi JS, Abdulrahman AY, Rothan HA (2021) Doxycycline interferes with Zika virus serine protease and inhibits virus replication in human skin fibroblasts. Molecules 26(14):4321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Shiryaev SA, Farhy C, Pinto A, Huang CT, Simonetti N, Ngono AE, Dewing A, Shresta S, Pinkerton AB, Cieplak P, Strongin AY (2017) Characterization of the Zika virus two-component NS2B-NS3 protease and structure-assisted identification of allosteric small-molecule antagonists. Antivir Res 143:218–229

    Article  CAS  PubMed  Google Scholar 

  158. Nitsche C, Zhang L, Weigel LF, Schilz J, Graf D, Bartenschlager R, Hilgenfeld R, Klein CD (2017) Peptide–boronic acid inhibitors of flaviviral proteases: medicinal chemistry and structural biology. J Med Chem 60(1):511–516

    Article  CAS  PubMed  Google Scholar 

  159. Jackman JA, Costa VV, Park S, Real AL, Park JH, Cardozo PL, Ferhan AR, Olmo IG, Moreira TP, Bambirra JL, Queiroz VF (2018) Therapeutic treatment of Zika virus infection using a brain-penetrating antiviral peptide. Nat Mater 17(11):971–977

    Article  CAS  PubMed  Google Scholar 

  160. Phoo WW, Zhang Z, Wirawan M, Chew EJ, Chew AB, Kouretova J, Steinmetzer T, Luo D (2018) Structures of Zika virus NS2B-NS3 protease in complex with peptidomimetic inhibitors. Antivir Res 160:17–24

    Article  CAS  PubMed  Google Scholar 

  161. Nitsche C, Passioura T, Varava P, Mahawaththa MC, Leuthold MM, Klein CD, Suga H, Otting G (2019) De novo discovery of nonstandard macrocyclic peptides as noncompetitive inhibitors of the Zika virus NS2B-NS3 protease. ACS Med Chem Lett 10(2):168–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Abdulrahman AY, Khazali AS, Teoh TC, Rothan HA, Yusof R (2019) Novel peptides inhibit zika NS2B-NS3 serine protease and virus replication in human hepatic cell line. Int J Pept Res Ther 25(4):1659–1668

    Article  CAS  Google Scholar 

  163. Sahoo M, Lingaraja Jena SD, Kumar S (2016) Virtual screening for potential inhibitors of NS3 protein of Zika virus. Genom Inform 14(3):104

    Article  Google Scholar 

  164. Byler KG, Ogungbe IV, Setzer WN (2016) In-silico screening for anti-Zika virus phytochemicals. J Mol Graph Model 69:78–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Fatima M, Khan MS, Rashid H, Mehmood A, Kanwal S, Rasheed MA, Jamil F (2018) Structure based virtual screening and molecular docking studies for identification of allosteric inhibitors against Zika virus protease NS2B-NS3. Pak J Zool 50(5):1709–1715

    Article  CAS  Google Scholar 

  166. Rohini K, Agarwal P, Preethi B, Shanthi V, Ramanathan K (2019) Exploring the lead compounds for Zika virus NS2B-NS3 protein: an e-pharmacophore-based approach. Appl Biochem Biotechnol 187(1):194–210

    Article  CAS  PubMed  Google Scholar 

  167. Bowen LR, Li DJ, Nola DT, Anderson MO, Heying M, Groves AT, Eagon S (2019) Identification of potential Zika virus NS2B-NS3 protease inhibitors via docking, molecular dynamics and consensus scoring-based virtual screening. J Mol Model 25(7):1

    Article  CAS  Google Scholar 

  168. Choudhry H, Alzahrani FA, Hassan MA, Alghamdi A, Abdulaal WH, Bakhrebah MA, Zamzami MA, Helmi N, Bokhari FF, Zeyadi M, Baothman OA (2019) Zika virus targeting by screening inhibitors against NS2B/NS3 protease. Biomed Res Int. https://doi.org/10.1155/2019/3947245

    Article  PubMed  PubMed Central  Google Scholar 

  169. Thirumoorthy GS, Tarachand SP, Nagella P, Veerappa Lakshmaiah V (2021) Identification of potential ZIKV NS2B-NS3 protease inhibitors from Andrographis paniculata: an in-silico approach. J Biomol Struct Dyn. https://doi.org/10.1080/07391102.2021.1956592

    Article  PubMed  Google Scholar 

  170. Shin HJ, Kim MH, Lee JY, Hwang I, Yoon GY, Kim HS, Kwon YC, Ahn DG, Kim KD, Kim BT, Kim SJ (2021) Structure-based virtual screening: identification of a novel NS2B-NS3 protease inhibitor with potent antiviral activity against Zika and Dengue viruses. Microorganisms 9(3):545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Zhao B, Yi G, Du F, Chuang YC, Vaughan RC, Sankaran B, Kao CC, Li P (2017) Structure and function of the Zika virus full-length NS5 protein. Nat Commun 8(1):1–9

    Article  CAS  Google Scholar 

  172. Zmurko J, Marques RE, Schols D, Verbeken E, Kaptein SJ, Neyts J (2016) The viral polymerase inhibitor 7-deaza-2’-C-methyladenosine is a potent inhibitor of in vitro Zika virus replication and delays disease progression in a robust mouse infection model. PLoS Negl Trop Dis 10(5):e0004695

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Xu HT, Hassounah SA, Colby-Germinario SP, Oliveira M, Fogarty C, Quan Y, Han Y, Golubkov O, Ibanescu I, Brenner B, Stranix BR (2017) Purification of Zika virus RNA-dependent RNA polymerase and its use to identify small-molecule Zika inhibitors. J Antimicrob Chemother 72(3):727–734

    CAS  PubMed  Google Scholar 

  174. Bullard-Feibelman KM, Govero J, Zhu Z, Salazar V, Veselinovic M, Diamond MS, Geiss BJ (2017) The FDA-approved drug sofosbuvir inhibits Zika virus infection. Antivir Res 137:134–140

    Article  CAS  PubMed  Google Scholar 

  175. Wang C, Yang SN, Smith K, Forwood JK, Jans DA (2017) Nuclear import inhibitor N-(4-hydroxyphenyl) retinamide targets Zika virus (ZIKV) nonstructural protein 5 to inhibit ZIKV infection. Biochem Biophys Res Commun 493(4):1555–1559

    Article  CAS  PubMed  Google Scholar 

  176. Lu G, Bluemling GR, Collop P, Hager M, Kuiper D, Gurale BP, Painter GR, De La Rosa A, Kolykhalov AA (2017) Analysis of ribonucleotide 5′-triphosphate analogs as potential inhibitors of Zika virus RNA-dependent RNA polymerase by using nonradioactive polymerase assays. Antimicrob Agents Chemother 61(3):e01967-e2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Tong X, Smith J, Bukreyeva N, Koma T, Manning JT, Kalkeri R, Kwong AD, Paessler S (2018) Merimepodib, an IMPDH inhibitor, suppresses replication of Zika virus and other emerging viral pathogens. Antivir Res 149:34–40

    Article  CAS  PubMed  Google Scholar 

  178. Yang S, Xu M, Lee EM, Gorshkov K, Shiryaev SA, He S, Sun W, Cheng YS, Hu X, Tharappel AM, Lu B (2018) Emetine inhibits Zika and Ebola virus infections through two molecular mechanisms: inhibiting viral replication and decreasing viral entry. Cell Discov 4(1):1–4

    Article  CAS  Google Scholar 

  179. Pattnaik A, Palermo N, Sahoo BR, Yuan Z, Hu D, Annamalai AS, Vu HL, Correas I, Prathipati PK, Destache CJ, Li Q (2018) Discovery of a non-nucleoside RNA polymerase inhibitor for blocking Zika virus replication through in silico screening. Antivir Res 151:78–86

    Article  CAS  PubMed  Google Scholar 

  180. Lin Y, Zhang H, Song W, Si S, Han Y, Jiang J (2019) Identification and characterization of Zika virus NS5 RNA-dependent RNA polymerase inhibitors. Int J Antimicrob Agents 54(4):502–506

    Article  CAS  PubMed  Google Scholar 

  181. Gharbi-Ayachi A, Santhanakrishnan S, Wong YH, Chan KW, Tan ST, Bates RW, Vasudevan SG, El Sahili A, Lescar J (2020) Non-nucleoside inhibitors of Zika virus RNA-dependent RNA polymerase. J Virol 94(21):e00794-e820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Yuan J, Yu J, Huang Y, He Z, Luo J, Wu Y, Zheng Y, Wu J, Zhu X, Wang H, Li M (2020) Antibiotic fidaxomicin is an RdRp inhibitor as a potential new therapeutic agent against Zika virus. BMC Med 18(1):1–6

    Article  CAS  Google Scholar 

  183. Chen Y, Li Z, Pan P, Lao Z, Xu J, Li Z, Zhan S, Liu X, Wu Y, Wang W, Li G (2021) Cinnamic acid inhibits Zika virus by inhibiting RdRp activity. Antivir Res 192:105117

    Article  CAS  PubMed  Google Scholar 

  184. Sáez-Álvarez Y, Jiménez de Oya N, Del Águila C, Saiz JC, Arias A, Agudo R, Martín-Acebes MA (2021) Novel non-nucleoside inhibitors of Zika virus polymerase identified through the screening of an open library of anti-kynetoplastid compounds. Antimicrob Agents Chemother. https://doi.org/10.1128/AAC.00894-21

    Article  PubMed  PubMed Central  Google Scholar 

  185. Stephen P, Baz M, Boivin G, Lin SX (2016) Structural insight into NS5 of Zika virus leading to the discovery of MTase inhibitors. J Am Chem Soc 138(50):16212–16215

    Article  CAS  PubMed  Google Scholar 

  186. Hercik K, Brynda J, Nencka R, Boura E (2017) Structural basis of Zika virus methyltransferase inhibition by sinefungin. Adv Virol 162(7):2091–2096

    CAS  Google Scholar 

  187. Hernandez J, Hoffer L, Coutard B, Querat G, Roche P, Morelli X, Decroly E, Barral K (2019) Optimization of a fragment linking hit toward Dengue and Zika virus NS5 methyltransferases inhibitors. Eur J Med Chem 161:323–333

    Article  CAS  PubMed  Google Scholar 

  188. Spizzichino S, Mattedi G, Lauder K, Valle C, Aouadi W, Canard B, Decroly E, Kaptein SJ, Neyts J, Graham C, Sule Z (2020) Design, synthesis and discovery of N, N’-carbazoyl-aryl-urea Inhibitors of Zika NS5 methyltransferase and virus replication. ChemMedChem 15(4):385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Song W, Zhang H, Zhang Y, Chen Y, Lin Y, Han Y, Jiang J (2021) Identification and characterization of Zika Virus NS5 methyltransferase inhibitors. Front Cell Infect Microbiol 11:267

    Article  Google Scholar 

  190. Elfiky AA (2016) Zika viral polymerase inhibition using anti-HCV drugs both in market and under clinical trials. J Med Virol 88(12):2044–2051

    Article  PubMed  Google Scholar 

  191. Singh A, Jana NK (2017) Discovery of potential Zika virus RNA polymerase inhibitors by docking-based virtual screening. Comput Biol Chem 71:144–151

    Article  CAS  PubMed  Google Scholar 

  192. Ramharack P, Soliman ME (2018) Zika virus NS5 protein potential inhibitors: an enhanced in silico approach in drug discovery. J Biomol Struct Dyn 36(5):1118–1133

    Article  CAS  PubMed  Google Scholar 

  193. Elfiky AA (2020) Novel guanosine derivatives against Zika virus polymerase in silico. J Med Virol 92(1):11–16

    Article  CAS  PubMed  Google Scholar 

  194. Ali R, Badshah SL, Faheem M, Abbasi SW, Ullah R, Bari A, Jamal SB, Mahmood HM, Haider A, Haider S (2020) Identification of potential inhibitors of Zika virus NS5 RNA-dependent RNA polymerase through virtual screening and molecular dynamic simulations. Saudi Pharm J 28(12):1580–1591

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Zhang C, Feng T, Cheng J, Li Y, Yin X, Zeng W, Jin X, Li Y, Guo F, Jin T (2017) Structure of the NS5 methyltransferase from Zika virus and implications in inhibitor design. Biochem Biophys Res Commun 492(4):624–630

    Article  CAS  PubMed  Google Scholar 

  196. Santos FR, Lima WG, Maia EH, Assis LC, Davyt D, Taranto AG, Ferreira JM (2020) Identification of a potential Zika virus inhibitor targeting NS5 methyltransferase using virtual screening and molecular dynamics simulations. J Chem Inf Model 60(2):562–568

    Article  CAS  PubMed  Google Scholar 

  197. Bharadwaj S, Rao AK, Dwivedi VD, Mishra SK, Yadava U (2021) Structure-based screening and validation of bioactive compounds as Zika virus methyltransferase (MTase) inhibitors through first-principle density functional theory, classical molecular simulation and QM/MM affinity estimation. J Biomol Struct Dyn 39(7):2338–2351

    Article  CAS  PubMed  Google Scholar 

  198. Kingwell K (2021) Pan-serotype antiviral for dengue infection. Nat Rev Microbiol 19(4):221

    Article  CAS  PubMed  Google Scholar 

  199. Scroggs SL, Gass JT, Chinnasamy R, Widen SG, Azar SR, Rossi SL, Arterburn JB, Vasilakis N, Hanley KA (2021) Evolution of resistance to fluoroquinolones by dengue virus serotype 4 provides insight into mechanism of action and consequences for viral fitness. Virology 552:94–106

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Shobana Sundar thanks the Indian Council of Medical Research (ICMR) for the financial support through the award of Research Associateship (ISRM/11(13)/2019). The authors also thank the Department of Bioinformatics, Bharathiar University for the computational facilities.

Author information

Authors and Affiliations

  1. Computational Biology Lab, Department of Bioinformatics, Bharathiar University, Coimbatore, India

    Shobana Sundar & Shanmughavel Piramanayagam

  2. Data Mining and Text Mining Laboratory, Department of Bioinformatics, Bharathiar University, Coimbatore, Tamil Nadu, India

    Jeyakumar Natarajan

Authors
  1. Shobana Sundar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shanmughavel Piramanayagam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeyakumar Natarajan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: SS, SP, JN; Writing—original draft preparation: SS; Writing—review and editing: SP, JN; Supervision: SP, JN.

Corresponding author

Correspondence to Jeyakumar Natarajan.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Informed consent

As the study does not involve any human participants and/or Animals, consent from the participants is not required for this study.

Research involving human participants and/or animals statement

The authors declare that the study does not involve any human participants and/or Animals.

Additional information

Edited by Detlev H. Kruger.

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sundar, S., Piramanayagam, S. & Natarajan, J. A review on structural genomics approach applied for drug discovery against three vector-borne viral diseases: Dengue, Chikungunya and Zika. Virus Genes 58, 151–171 (2022). https://doi.org/10.1007/s11262-022-01898-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11262-022-01898-5

Keywords

Search

Navigation