Structure Based Identification of Potential Inhibitors of NS3 Protein of Zika Virus

Author(s): Md. Imam Faizan, Abu Turab Naqvi, Md. Imtaiyaz Hassan, Mohd. Abdullah, Ayesha Tazeen, Zoya Shafat, Malik Hisamuddin, Aftab Alam, Shahnawaz Ali, Sher Ali, Anam Farooqui, Abu Hamza, Nazish Parveen, Farah Deeba, Anwar Ahmed, Shama Parveen*.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 7 , 2019

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Graphical Abstract:


Background: The re-emerging Zika virus has posed a serious threat to human health due to its association with the neurological disorders. The NS3 protein of Zika virus plays a pivotal role in the genome replication and thus may prove to be a critical target for the drug designing studies.

Objective: The present study was conceptualized to analyze the crystal structure of NS3 protein of Zika virus followed by the identification of it’s potential inhibitors.

Methods: Crystal structure of the NS3 protein was evaluated in detail. Docking of the NS3 protein was done with 130 different ligands including dengue virus inhibitors and their similar compounds along with some approved drugs. The drug likeliness properties were checked for non drug compounds.

Results: Structural analysis of the NS3 protein revealed three important sites namely ATP- and RNAbinding sites as well as a central cavity. The selected ten ligands (ZINC05487635, ZINC0092398, ZINC13345444, 4-methoxyphenyl 4-chloro-3-nitrobenzoate, Luteolin, Ivermectin, Suramin, Dasatinib, Panduratin A, and ARDP0009) showed a higher binding affinity for the NS3 protein and good drug likeliness properties.

Conclusion: These inhibitors could possibly act as potential lead molecules for future drug designing studies. Our present computational data is envisaged to be useful for gathering experimental evidences towards the development of potential therapeutic molecules against this arthropod mediated pathogen.

Keywords: Zika virus, NS3 protein, inhibitors, antiviral drugs, molecular docking, structure based drug design and discovery.

Musso, D.; Roche, C.; Robin, E.; Nhan, T.; Teissier, A.; Cao-Lormeau, V-M. Potential sexual transmission of Zika virus. Emerg. Infect. Dis., 2015, 21(2), 359.
Macnamara, F. Zika virus: A report on three cases of human infection during an epidemic of jaundice in Nigeria. Trans. R. Soc. Trop. Med. Hyg., 1954, 48(2), 139-145.
Besnard, M.; Lastere, S.; Teissier, A.; Cao-Lormeau, V.; Musso, D. Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill., 2014, 19(13), 20751.
Musso, D.; Nhan, T.; Robin, E.; Roche, C.; Bierlaire, D.; Zisou, K.; Shan, Yan A.; Cao-Lormeau, V.; Broult, J. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill., 2014, 19(14), 20761.
Faizan, M.I.; Abdullah, M.; Ali, S.; Naqvi, I.H.; Ahmed, A.; Parveen, S. Zika virus-induced microcephaly and its possible molecular mechanism. Intervirology, 2016, 59(3), 152-158.
Dos Santos, T.; Rodriguez, A.; Almiron, M.; Sanhueza, A.; Ramon, P.; de Oliveira, W.K.; Coelho, G.E.; Badaró, R.; Cortez, J.; Ospina, M. Zika virus and the Guillain-Barré syndrome-case series from seven countries. N. Engl. J. Med., 2016, 375(16), 1598-1601.
WHO. Zika virus, microcephaly and Guillain-Barré syndrome situation report. [Accession date 10th March 2017]
Sirohi, D.; Chen, Z.; Sun, L.; Klose, T.; Pierson, T.C.; Rossmann, M.G.; Kuhn, R.J. The 3.8 Å resolution cryo-EM structure of Zika virus. Science, 2016, 352(6284), 467-470.
Baronti, C.; Piorkowski, G.; Charrel, R.N.; Boubis, L.; Leparc-Goffart, I.; de Lamballerie, X. Complete coding sequence of zika virus from a French polynesia outbreak in 2013. Genome Announc., 2014, 2(3), e00500-e00514.
Jain, R.; Coloma, J.; García-Sastre, A.; Aggarwal, A.K. Structure of the NS3 helicase from Zika virus. Nat. Struct. Mol. Biol., 2016, 23(8), 752-754.
Bollati, M.; Alvarez, K.; Assenberg, R.; Baronti, C.; Canard, B.; Cook, S.; Coutard, B.; Decroly, E.; de Lamballerie, X.; Gould, E.A. Structure and functionality in flavivirus NS-proteins: Perspectives for drug design. Antiviral Res., 2010, 87(2), 125-148.
Amberg, S.M.; Nestorowicz, A.; McCourt, D.W.; Rice, C.M. NS2B-3 proteinase-mediated processing in the yellow fever virus structural region: In vitro and in vivo studies. J. Virol., 1994, 68(6), 3794-3802.
Yamshchikov, V.F.; Compans, R.W. Processing of the intracellular form of the west Nile virus capsid protein by the viral NS2B-NS3 protease: An in vitro study. J. Virol., 1994, 68(9), 5765-5771.
Chambers, T.J.; Weir, R.C.; Grakoui, A.; McCourt, D.W.; Bazan, J.F.; Fletterick, R.J.; Rice, C.M. 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. USA, 1990, 87(22), 8898-8902.
Tian, H.; Ji, X.; Yang, X.; Xie, W.; Yang, K.; Chen, C.; Wu, C.; Chi, H.; Mu, Z.; Wang, Z. The crystal structure of Zika virus helicase: Basis for antiviral drug design. Protein Cell, 2016, 7(6), 450-454.
Cao, X.; Li, Y.; Jin, X.; Li, Y.; Guo, F.; Jin, T. Molecular mechanism of divalent-metal-induced activation of NS3 helicase and insights into Zika virus inhibitor design. Nucleic Acids Res., 2016, 44(21), 10505-10514.
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The Protein Data Bank, 1999. In: International Tables for Crystallography Volume F: Crystallography of biological macromolecules; Springer:, 2006; p. 675- 684.
Kuhn, R.J.; Zhang, W.; Rossmann, M.G.; Pletnev, S.V.; Corver, J.; Lenches, E.; Jones, C.T.; Mukhopadhyay, S.; Chipman, P.R.; Strauss, E.G. Structure of dengue virus: Implications for flavivirus organization, maturation, and fusion. Cell, 2002, 108(5), 717-725.
Zhang, X.; Ge, P.; Yu, X.; Brannan, J.M.; Bi, G.; Zhang, Q.; Schein, S.; Zhou, Z.H. Cryo-EM structure of the mature dengue virus at 3.5-Å resolution. Nat. Struct. Mol. Biol., 2013, 20(1), 105-110.
Narayana, K.R.; Reddy, M.S.; Chaluvadi, M.; Krishna, D. Bioflavonoids classification, pharmacological, biochemical effects and therapeutic potential. Indian J. Pharmacol., 2001, 33(1), 2-16.
Zandi, K.; Teoh, B-T.; Sam, S-S.; Wong, P-F.; Mustafa, M.R.; AbuBakar, S. Antiviral activity of four types of bioflavonoid against dengue virus type-2. Virol. J., 2011, 8(1), 560.
Kiat, T.S.; Pippen, R.; Yusof, R.; Ibrahim, H.; Khalid, N.; Rahman, N.A. Inhibitory activity of cyclohexenyl chalcone derivatives and flavonoids of fingerroot, Boesenbergia rotunda(L.), towards dengue-2 virus NS3 protease. Bioorg. Med. Chem. Lett., 2006, 16(12), 3337-3340.
Tomlinson, S.M.; Malmstrom, R.D.; Russo, A.; Mueller, N.; Pang, Y-P.; Watowich, S.J. Structure-based discovery of dengue virus protease inhibitors. Antiviral Res., 2009, 82(3), 110-114.
Keivan, Z.; Teoh, B-T.; Sam, S-S.; Wong, P-F.; Mustafa, M.R.; AbuBakar, S. In vitro antiviral activity of fisetin, rutin and naringenin against dengue virus type-2. J. Med. Plants Res., 2011, 5(23), 5534-5539.
Sanchez, I.; Gómez‐Garibay, F.; Taboada, J.; Ruiz, B. Antiviral effect of flavonoids on the dengue virus. Phytother. Res., 2000, 14(2), 89-92.
Chiow, K.; Phoon, M.; Putti, T.; Tan, B.K.; Chow, V.T. Evaluation of antiviral activities of Houttuynia cordata Thunb. Extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection. Asian Pac. J. Trop. Med., 2016, 9(1), 1-7.
Kim, S.; Thiessen, P.A.; Bolton, E.E.; Chen, J.; Fu, G.; Gindulyte, A.; Han, L.; He, J.; He, S.; Shoemaker, B.A. PubChem substance and compound databases. Nucleic Acids Res., 2015, 44(D1), D1202-D1213.
Irwin, J.J.; Sterling, T.; Mysinger, M.M.; Bolstad, E.S.; Coleman, R.G. ZINC: A free tool to discover chemistry for biology. J. Chem. Inf. Model., 2012, 52(7), 1757-1768.
Basavannacharya, C.; Vasudevan, S.G. Suramin inhibits helicase activity of NS3 protein of dengue virus in a fluorescence-based high throughput assay format. Biochem. Biophys. Res. Commun., 2014, 453(3), 539-544.
Mastrangelo, E.; Pezzullo, M.; De Burghgraeve, T.; Kaptein, S.; Pastorino, B.; Dallmeier, K.; de Lamballerie, X.; Neyts, J.; Hanson, A.M.; Frick, D.N. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: New prospects for an old drug. J. Antimicrob. Chemother., 2012, 67(8), 1884-1894.
de Wispelaere, M.; LaCroix, A.J.; Yang, P.L. The small molecules AZD0530 and dasatinib inhibit dengue virus RNA replication via Fyn kinase. J. Virol., 2013, 87(13), 7367-7381.
Grosdidier, A.; Zoete, V.; Michielin, O. SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Res, 2011, 39(suppl_2), W270-W277.
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
Alam, A.; Tamkeen, N.; Imam, N.; Farooqui, A.; Ahmed, M.M.; Tazyeen, S.; Ali, S.; Malik, M.Z.; Ishrat, R. Pharmacokinetic and molecular docking studies of plant-derived natural compounds to exploring potential anti-alzheimer activity.In Silico Approach for Sustainable Agriculture; Springer, 2018, pp. 217-238.
Arup, K. Ghose, Vellarkad N. Viswanadhan, John J. Wendoloski. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem., 1999, 1(1), 55-68.
Seeliger, D.; de Groot, B.L. Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J. Comput. Aided Mol. Des., 2010, 24(5), 417-422.
DeLano, W.L. The PyMOL molecular graphics system; Palo Alto, CA, USA, 2002.
Wallace, A.C.; Laskowski, R.A.; Thornton, J.M. LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Protein Eng. Des. Sel., 1995, 8(2), 127-134.
Ahsan, M.J.; Samy, J.G.; Khalilullah, H.; Nomani, M.S.; Saraswat, P.; Gaur, R.; Singh, A. Molecular properties prediction and synthesis of novel 1,3,4-oxadiazole analogues as potent antimicrobial and antitubercular agents. Bioorg. Med. Chem. Lett., 2011, 21(24), 7246-7250.
Bavan, S.; Sherman, B.; Luetje, C.W.; Abaffy, T. Discovery of novel ligands for mouse olfactory receptor MOR42-3 using an in silico screening approach and in vitro validation. PLoS One, 2014, 9(3), e92064.
Gruba, N.; Rodriguez Martinez, J.I.; Grzywa, R.; Wysocka, M.; Skoreński, M.; Burmistrz, M.; Łęcka, M.; Lesner, A.; Sieńczyk, M.; Pyrć, K. Substrate profiling of Zika virus NS2B‐NS3 protease. FEBS Lett., 2016, 590(20), 3459-3468.
Tian, H.; Ji, X.; Yang, X.; Zhang, Z.; Lu, Z.; Yang, K.; Chen, C.; Zhao, Q.; Chi, H.; Mu, Z. Structural basis of Zika virus helicase in recognizing its substrates. Protein Cell, 2016, 7(8), 562-570.
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings1. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
van de Waterbeemd, H.; Camenisch, G.; Folkers, G.; Chretien, J.R.; Raevsky, O.A. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J. Drug Target., 1998, 6(2), 151-165.
Veber, D.F.; Johnson, S.R.; Cheng, H-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
Klages, J.; Coles, M.; Kessler, H. NMR-based screening: A powerful tool in fragment-based drug discovery. Analyst, 2007, 132(7), 692-705.
Blake, J.F. Examination of the computed molecular properties of compounds selected for clinical development. Biotechniques, 2003, 34, S16-S20.
Abdullah, M.; Sher Ali, A.T.; Naqvi, I.H.; Verma, H.N.; Ahmed, A.; Kazim, S.N.; Parveen, S. Zika viral infection and its future prospects. Indian J. Health Sci. Care, 2016, 3(2), 78-84.
Badshah, S.L.; Naeem, A.; Mabkhot, Y. The new high resolution crystal structure of NS2B-NS3 protease of Zika virus. Viruses, 2017, 9(1), 7.
Li, Y.; Zhang, Z.; Phoo, W.W.; Loh, Y.R.; Wang, W.; Liu, S.; Chen, M.W.; Hung, A.W.; Keller, T.H.; Luo, D. Structural dynamics of Zika virus NS2B-NS3 protease binding to dipeptide inhibitors. Structure, 2017, 25(8), 1242-1250.
Lee, H.; Ren, J.; Nocadello, S.; Rice, A.J.; Ojeda, I.; Light, S.; Minasov, G.; Vargas, J.; Nagarathnam, D.; Anderson, W.F. Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus. Antiviral Res., 2017, 139, 49-58.
Mottin, M.; Braga, R.C.; da Silva, R.A.; da Silva, J.H.M.; Perryman, A.L.; Ekins, S.; Andrade, C.H. Molecular dynamics simulations of Zika virus NS3 helicase: Insights into RNA binding site activity. Biochem. Biophys. Res. Commun., 2017, 492(4), 643-651.
Xu, M.; Lee, E.M.; Wen, Z.; Cheng, Y.; Huang, W-K.; Qian, X.; Julia, T.; Kouznetsova, J.; Ogden, S.C.; Hammack, C. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat. Med., 2016, 22(10), 1101.
Andrews, K.T.; Fisher, G.; Skinner-Adams, T.S. Drug repurposing and human parasitic protozoan diseases. Int. J. Parasitol. Drugs Drug Resist., 2014, 4(2), 95-111.
Sanseau, P.; Koehler, J. Computational methods for drug repurposing; Oxford University Press, 2011.
Liu, S.; Ewing, M.; Anglard, P.; Trahan, E.; La Rocca, R.V.; Myers, C.E.; Linehan, W.M. The effect of suramin, tumor necrosis factor and interferon γ on human prostate carcinoma. J. Urol., 1991, 145(2), 389-392.
Wagstaff, K.M.; Sivakumaran, H.; Heaton, S.M.; Harrich, D.; Jans, D.A. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem. J., 2012, 443(3), 851-856.
Campbell, W.C. Ivermectin and abamectin; Springer Science & Business Media, 2012.
Gratacap, M-P.; Martin, V.; Valéra, M-C.; Allart, S.; Garcia, C.; Sié, P.; Recher, C.; Payrastre, B. The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo. Blood, 2009, 114(9), 1884-1892.
Tjioe, K.C.; Tostes Oliveira, D.; Gavard, J. luteolin impacts on the dna damage pathway in oral squamous cell carcinoma. Nutr. Cancer, 2016, 68(5), 838-847.

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Year: 2019
Page: [761 - 774]
Pages: 14
DOI: 10.2174/1570180815666180821105012
Price: $65

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