Abstract
Amongst the neglected tropical diseases, dengue remains a disease of concern, and the rise of global temperatures every year puts additional liabilities on the infrastructure of the health sector of various underdeveloped and developing countries. Increasing incidence puts additional stress on an already burdened healthcare infrastructures. This calls for an urgent need of discovering an inhibitor for Dengue virus (DENV). The success in targeting HIV and HCV proteases has driven considerable attention of researchers to explore the same towards the DENV NS2B-NS3 protease. Although most attempts yet remains futile, advancing computational power and biotechnology can certainly play a pivotal role in speeding up the drug discovery process. High-throughput Virtual Screening is one such frontier that could help screening of large libraries of chemical entities, making the in vitro pipeline efficient and cost effective. This chapter presents the DENV NS2B-NS3 protease inhibitors identified through High-throughput Virtual Screening and its impact on drug development against the Dengue virus.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Akgün H, Karamelekoglu I, Berk B, et al. Synthesis and antimycobacterial activity of some phthalimide derivatives. Bioorganic Med Chem. 2012;20:4149–54. https://doi.org/10.1016/j.bmc.2012.04.060.
Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature. 2013;496:504–7. https://doi.org/10.1038/nature12060.
Bhowmick S, Alissa SA, Wabaidur SM, et al. Structure-guided screening of chemical database to identify NS3-NS2B inhibitors for effective therapeutic application in dengue infection. J Mol Recognit. 2020;33:1–18. https://doi.org/10.1002/jmr.2838.
Davis BW, Diep JT, Jose S. (12) United States Patent 2. 2017.
De Clercq E. Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int J Antimicrob Agents. 2009;33:307–20. https://doi.org/10.1016/j.ijantimicag.2008.10.010.
Deng J, Li N, Liu H, et al. Discovery of novel small molecule inhibitors of dengue viral NS2B-NS3 protease using virtual screening and scaffold hopping. J Med Chem. 2012;55:6278–93. https://doi.org/10.1021/jm300146f.
Ebrahim GJ. Dengue and dengue haemorrhagic fever. J Trop Pediatr. 1993;39:262–3. https://doi.org/10.1093/tropej/39.5.262.
Erbel P, Schiering N, D’Arcy A, et al. Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus. Nat Struct Mol Biol. 2006;13:372–3. https://doi.org/10.1038/nsmb1073.
Falgout B, Pethel M, Zhang YM, Lai CJ. Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins. J Virol. 1991;65:2467–75. https://doi.org/10.1128/jvi.65.5.2467-2475.1991.
Ganesh VK, Muller N, Judge K, et al. Identification and characterization of nonsubstrate based inhibitors of the essential dengue and West Nile virus proteases. Bioorganic Med Chem. 2005;13:257–64. https://doi.org/10.1016/j.bmc.2004.09.036.
Goncalvez AP, Engle RE, St. Claire M, et al. Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention. Proc Natl Acad Sci USA. 2007;104:9422–7. https://doi.org/10.1073/pnas.0703498104.
Guy B, Noriega F, Ochiai RL, et al. A recombinant live attenuated tetravalent vaccine for the prevention of dengue. Expert Rev Vaccines. 2017;16:671–83. https://doi.org/10.1080/14760584.2017.1335201.
Guzman MG, Halstead SB, Artsob H, et al. Dengue: a continuing global threat. Nat Rev Microbiol. 2010;8:S7–16. https://doi.org/10.1038/nrmicro2460.
Hariono M, Choi SB, Roslim RF, et al. Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: virtual screening, synthesis, biological evaluation and molecular modelling. PLoS ONE. 2019;14:1–21. https://doi.org/10.1371/journal.pone.0210869.
Heh CH, Othman R, Buckle MJC, et al. Rational discovery of dengue type 2 non-competitive inhibitors. Chem Biol Drug Des. 2013;82:1–11. https://doi.org/10.1111/cbdd.12122.
Knehans T, Schüller A, Doan DN, et al. Structure-guided fragment-based in silico drug design of dengue protease inhibitors. J Comput Aided Mol Des. 2011;25:263–74. https://doi.org/10.1007/s10822-011-9418-0.
Korb O. Efficient ant colony optimization algorithms for structure- and ligand-based drug design. Chem Cent J. 2009;3:247–58. https://doi.org/10.1186/1752-153X-3-S1-O10.
Lampa AK, Bergman SM, Gustafsson SS, et al. Novel peptidomimetic hepatitis C virus NS3/4A protease inhibitors spanning the P2–P1′ region. ACS Med Chem Lett. 2014;5:249–54. https://doi.org/10.1021/ml400217r.
Le Grand S, Götz AW, Walker RC. SPFP: Speed without compromise—a mixed precision model for GPU accelerated molecular dynamics simulations. Comput Phys Commun. 2013;184:374–80. https://doi.org/10.1016/j.cpc.2012.09.022.
Li L, Basavannacharya C, Chan KWK, et al. Structure-guided discovery of a novel non-peptide inhibitor of dengue virus NS2B-NS3 protease. Chem Biol Drug Des. 2015;86:255–64. https://doi.org/10.1111/cbdd.12500.
Matsushita M, Ozaki Y, Hasegawa Y, et al. A novel phthalimide derivative, TC11, has preclinical effects on high-risk myeloma cells and osteoclasts. PLoS ONE. 2015;10:1–15. https://doi.org/10.1371/journal.pone.0116135.
Mukhopadhyay S, Kuhn RJ, Rossmann MG. A structural perspective of the Flavivirus life cycle. Nat Rev Microbiol. 2005;3:13–22. https://doi.org/10.1038/nrmicro1067.
Nestorowicz A, Chambers TJ, Rice CM. Mutagenesis of the yellow fever virus NS2A/2B cleavage site: effects on proteolytic processing, viral replication, and evidence for alternative processing of the NS2A protein. Virology. 1994;199:114–23. https://doi.org/10.1006/viro.1994.1103.
Nguyen TTH, Lee S, Wang HK, et al. In vitro evaluation of novel inhibitors against the NS2B-NS3 protease of dengue fever virus type 4. Molecules. 2013;18:15600–12. https://doi.org/10.3390/molecules181215600.
Noble CG, Seh CC, Chao AT, Shi PY. Ligand-bound structures of the dengue virus protease reveal the active conformation. J Virol. 2012;86:438–46. https://doi.org/10.1128/JVI.06225-11.
Pambudi S, Kawashita N, Phanthanawiboon S, et al. A small compound targeting the interaction between nonstructural proteins 2B and 3 inhibits dengue virus replication. Biochem Biophys Res Commun. 2013;440:393–8. https://doi.org/10.1016/j.bbrc.2013.09.078.
Pelliccia S, Wu YH, Coluccia A, et al. Inhibition of dengue virus replication by novel inhibitors of RNA-dependent RNA polymerase and protease activities. J Enzyme Inhib Med Chem. 2017;32:1091–101. https://doi.org/10.1080/14756366.2017.1355791.
Phong WY, Moreland NJ, Siew P, et al. Dengue protease activity: the structural integrity and interaction of NS2B with NS3 protease and its potential as a drug target. Biosci Rep. 2011;31:399–409. https://doi.org/10.1042/BSR20100142.
Selvam P, Lakra DR, Pannecouque C, De Clercq E. Synthesis, antiviral and cytotoxicity studies of novel N-substituted indophenazine derivatives. Indian J Pharm Sci. 2012;74:274–8. https://doi.org/10.4103/0250-474X.106077.
Timiri AK, Subasri S, Kesherwani M, et al. Synthesis and molecular modelling studies of novel sulphonamide derivatives as dengue virus 2 protease inhibitors. Bioorg Chem. 2015;62:74–82. https://doi.org/10.1016/j.bioorg.2015.07.005.
Tomlinson SM, Malmstrom RD, Russo A, et al. Structure-based discovery of dengue virus protease inhibitors. Antiviral Res. 2009;82:110–4. https://doi.org/10.1016/j.antiviral.2009.02.190.
Viswanathan U, Tomlinson SM, Fonner JM, et al. Identification of a novel inhibitor of dengue virus protease through use of a virtual screening drug discovery web portal. J Chem Inf Model. 2014;54:2816–25. https://doi.org/10.1021/ci500531r.
WHO. Treatment, prevention and control global strategy for dengue prevention and control 2. 2012.
Wyles DL. Antiviral resistance and the future landscape of hepatitis C virus infection therapy. J Infect Dis. 2013;207:33–9. https://doi.org/10.1093/infdis/jis761.
Yusof R, Clum S, Wetzel M, et al. Purified NS2B/NS3 serine protease of dengue virus type 2 exhibits cofactor NS2B dependence for cleavage of substrates with dibasic amino acids in vitro. J Biol Chem. 2000;275:9963–9. https://doi.org/10.1074/jbc.275.14.9963.
Acknowledgements
The Authors thank DST-SERB, Govt. of India for providing financial support through their project (EMR/2016/005711/) dated 7th August 2017 and Birla Institute of Technology, Mesra, Ranchi, India for providing the necessary infrastructure support.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Murtuja, S., Shilkar, D., Sarkar, B., Sinha, B.N., Jayaprakash, V. (2021). Identification of Dengue NS2B-NS3 Protease Inhibitors Through High-Throughput Virtual Screening—Impacts on Drug Development Against the Dengue Virus. In: Ahmad, S.I. (eds) Human Viruses: Diseases, Treatments and Vaccines . Springer, Cham. https://doi.org/10.1007/978-3-030-71165-8_5
Download citation
DOI: https://doi.org/10.1007/978-3-030-71165-8_5
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-71164-1
Online ISBN: 978-3-030-71165-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)