Potential Alphavirus Inhibitors From Phytocompounds – Molecular Docking and Dynamics Based Approach
DOI:
https://doi.org/10.20535/ibb.2023.7.3.285245Keywords:
alphaviral diseases, glycoproteins, nsP2, nsP4, molecular docking, granatin AAbstract
Background. Alphaviral diseases are an economic burden all over the world due to their chronicity and distribution worldwide. The glycoproteins E1 and E2 are important for binding to the surface of the host cell by interacting with the receptors and non-structural proteins named nsP2 and nsP4 are important for the replication of virus, so can be an important drug discovery target.
Objective. We are aimed to explore the in silico interaction between plant-based compounds (phytocompounds) and specific protein targets, such as nonstructural protein nsP4 and glycoprotein E2 of Sindbis virus (SINV), nsP2 and E2 of Chikungunya virus (CHIKV), and glycoproteins E1 and E2 of Ross River virus (RRV).
Methods. A library of phytochemicals from Indian medicinal plants was prepared using databases and converted to 3D structures. Protein structures (nsP2, nsp4, E1, E2) were obtained and refined, followed by molecular docking with AutoDock Vina. Promising ligands were evaluated for properties, cytotoxicity, and mutagenicity, considering drug-likeness and potential issues. Molecular Dynamics simulations assessed complex stability.
Results. We analyzed 375 phytocompounds against these targets using molecular docking, modeling, and molecular dynamics for SINV, CHIKV, and Ross River (RRV) virus proteins. Granatin A has been found to successfully bind to the target sites of SINV nsP4, CHIKV E2, and CHIKV nsP2 with binding affinity values of -16.2, -20.6, and -18.6 Kcal/mol respectively. Further, stability of CHIKV E2 – Granatin A complex was done by performing molecular dynamic simulation and the complex was stable at 60ps.
Conclusions. This research provides valuable insights into the development of effective antiviral drugs against alphaviruses, emphasizing the importance of natural compounds and their interactions with viral proteins. This study might pave the way for further exploration of these small molecules as effective anti-alphaviral therapeutic agents.
References
Irwin KK, Renzette N, Kowalik TF, Jensen JD. Antiviral drug resistance as an adaptive process. Virus Evol. 2016;2(1):vew014. DOI: 10.1093/ve/vew014
Biswas D, Nandy S, Mukherjee A, Pandey DK, Dey A. Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review. South African J Bot. 2020;129:272-82. DOI: 10.1016/j.sajb.2019.07.049
Kapoor R, Sharma B, Kanwar SS. Antiviral phytochemicals: An overview. Biochem Physiol Open Access. 2017;06(02). DOI: 10.4172/2168-9652.1000220
Miner JJ, Aw-Yeang HX, Fox JM, Taffner S, Malkova ON, Oh ST, et al. Chikungunya viral arthritis in the United States: a mimic of seronegative rheumatoid arthritis. Arthritis Rheumatol (Hoboken, NJ). 2015;67(5):1214-20. DOI: 10.1002/art.39027
Brummer-Korvenkontio M, Vapalahti O, Kuusisto P, Saikku P, Koskela P, Nygren T, et al. Epidemiology of Sindbis virus infections in Finland 1981-96: possible factors explaining a peculiar disease pattern. Epidemiol Infect. 2002;129(2):335-45. DOI: 10.1017/s0950268802007409
Bergqvist J, Forsman O, Larsson P, Näslund J, Lilja T, Engdahl C, et al. Detection and isolation of Sindbis virus from mosquitoes captured during an outbreak in Sweden, 2013. Vector Borne Zoonotic Dis. 2015;15(2):133-40. DOI: 10.1089/vbz.2014.1717
Zeller H, Van Bortel W, Sudre B. Chikungunya: Its history in Africa and Asia and its spread to new regions in 2013-2014. J Infect Dis. 2016;214(suppl 5):S436-40. DOI: 10.1093/infdis/jiw391
Yactayo S, Staples JE, Millot V, Cibrelus L, Ramon-Pardo P. Epidemiology of Chikungunya in the Americas. J Infect Dis. 2016;214(suppl 5):S441-5. DOI: 10.1093/infdis/jiw390
Aaskov JG, Chen JY, Hanh NT, Dennington PM. Surveillance for Ross River virus infection using blood donors. Am J Trop Med Hyg. 1998;58(6):726-30. DOI: 10.4269/ajtmh.1998.58.726
Fauran P, Donaldson M, Harper J, Oseni RA, Aaskov JG. Characterization of Ross River viruses isolated from patients with polyarthritis in New Caledonia and Wallis and Futuna Islands. Am J Trop Med Hyg. 1984;33(6):1228-31. DOI: 10.4269/ajtmh.1984.33.1228
Smith AL, Tignor GH. Host cell receptors for two strains of Sindbis virus. Arch Virol. 1980;66(1):11-26. DOI: 10.1007/BF01315041
Das PK, Merits A, Lulla A. Functional cross-talk between distant domains of chikungunya virus non-structural protein 2 is decisive for its RNA-modulating activity. J Biol Chem. 2014;289(9):5635-53. DOI: 10.1074/jbc.M113.503433
Garmashova N, Gorchakov R, Frolova E, Frolov I. Sindbis virus nonstructural protein nsP2 is cytotoxic and inhibits cellular transcription. J Virol. 2006;80(12):5686-96. DOI: 10.1128/JVI.02739-05
Kamer G, Argos P. Primary structural comparison of RNA-dependent polymerases from plant, animal and bacterial viruses. Nucleic Acids Res. 1984;12(18):7269-82. DOI: 10.1093/nar/12.18.7269
O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform. 2011;3:33. DOI: 10.1186/1758-2946-3-33
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785-91. DOI: 10.1002/jcc.21256
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31(2):455-61. DOI: 10.1002/jcc.21334
Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717. DOI: 10.1038/srep42717
Banerjee P, Eckert AO, Schrey AK, Preissner R. ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res. 2018;46(W1):W257-63. DOI: 10.1093/nar/gky318
Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem 2023 update. Nucleic Acids Res. 2023 Jan 6;51(D1):D1373-80. DOI: 10.1093/nar/gkac956
Satomi H, Umemura K, Ueno A, Hatano T, Okuda T, Noro T. Carbonic anhydrase inhibitors from the pericarps of Punica granatum L. Biol Pharm Bull. 1993;16(8):787-90. DOI: 10.1248/bpb.16.787
Zahin M, Aqil F, Ahmad I. Broad spectrum antimutagenic activity of antioxidant active fraction of punica granatum L. peel extracts. Mutat Res. 2010;703(2):99-107. DOI: 10.1016/j.mrgentox.2010.08.001
Navaratnarajah CK, Kuhn RJ. Functional characterization of the Sindbis virus E2 glycoprotein by transposon linker-insertion mutagenesis. Virology. 2007;363(1):134-47. DOI: 10.1016/j.virol.2007.01.006
Mukhopadhyay S, Zhang W, Gabler S, Chipman PR, Strauss EG, Baker TS, et al. Mapping the structure and function of the E1 and E2 glycoproteins in alphaviruses. Structure. 2006;14(1):63-73. DOI: 10.1016/j.str.2005.07.025
Lim JY, Lee JH, Yun DH, Lee YM, Kim DK. Inhibitory effects of nodakenin on inflammation and cell death in lipopoly-saccharide-induced liver injury mice. Phytomedicine. 2021;81:153411. DOI: 10.1016/j.phymed.2020.153411
Rim HK, Cho W, Sung SH, Lee KT. Nodakenin suppresses lipopolysaccharide-induced inflammatory responses in macrophage cells by inhibiting tumor necrosis factor receptor-associated factor 6 and nuclear factor-κB pathways and protects mice from lethal endotoxin shock. J Pharmacol Exp Ther. 2012;342(3):654-64. DOI: 10.1124/jpet.112.194613
Rubach JK, Wasik BR, Rupp JC, Kuhn RJ, Hardy RW, Smith JL. Characterization of purified Sindbis virus nsP4 RNA-dependent RNA polymerase activity in vitro. Virology. 2009;384(1):201-8. DOI: 10.1016/j.virol.2008.10.030
Tan YB, Lello LS, Liu X, Law YS, Kang C, Lescar J, et al. Crystal structures of alphavirus nonstructural protein 4 (nsP4) reveal an intrinsically dynamic RNA-dependent RNA polymerase fold. Nucleic Acids Res. 2022;50(2):1000-16. DOI: 10.1093/nar/gkab1302
Venusova E, Kolesarova A, Horky P, Slama P. Physiological and immune functions of Punicalagin. Nutrients. 2021;13(7). DOI: 10.3390/nu13072150
Sahoo B, Chowdary TK. Conformational changes in Chikungunya virus E2 protein upon heparan sulfate receptor binding explain mechanism of E2-E1 dissociation during viral entry. Biosci Rep. 2019;39(6). DOI: 10.1042/BSR20191077
Powell LA, Miller A, Fox JM, Kose N, Klose T, Kim AS, et al. Human mAbs broadly protect against arthritogenic alpha-viruses by recognizing conserved elements of the Mxra8 receptor-binding site. Cell Host Microbe. 2020;28(5):699-711.e7. DOI: 10.1016/j.chom.2020.07.008
Salih EYA, Julkunen-Tiitto R, Luukkanen O, Fahmi MKM, Fyhrquist P. Hydrolyzable tannins (ellagitannins), flavonoids, pentacyclic triterpenes and their glycosides in antimycobacterial extracts of the ethnopharmacologically selected Sudanese medicinal plant Combretum hartmannianum Schweinf. Biomed Pharmacother. 2021;144:112264. DOI: 10.1016/j.biopha.2021.112264
Ahola T, Merits A. Functions of Chikungunya virus nonstructural proteins. In: Okeoma CM, editor. Chikungunya virus. Advances in biology, pathogenesis, and treatment. Springer Cham; 2016. pp. 75-98. DOI: 10.1007/978-3-319-42958-8_6
Narwal M, Singh H, Pratap S, Malik A, Kuhn RJ, Kumar P, et al. Crystal structure of chikungunya virus nsP2 cysteine protease reveals a putative flexible loop blocking its active site. Int J Biol Macromol. 2018;116:451-62. DOI: 10.1016/j.ijbiomac.2018.05.007
Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2021;49(D1):D1388-95. DOI: 10.1093/nar/gkaa971
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