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Prediction of binding potential of natural leads against the prioritized drug targets of chikungunya and dengue viruses by computational screening

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Abstract

The current study aimed to assess the binding potential of herbal lead molecules against the prioritized molecular targets of chikungunya virus (CHIKV) and dengue virus (DENV) by computational virtual screening and suggests a novel therapeutic intervention. Based on the metabolic pathway analysis and virulent functions, the non-structural and envelop proteins present in CHIKV and DENV were identified as putative drug targets. The structures of the protein not available in their native forms were computationally predicted by homology modeling. The lead compounds from 43 herbal sources were screened and their drug likeliness and pharmacokinetics properties were computationally predicted. The binding potential of selected phytoligands against the prioritized drug targets were analyzed by molecular docking studies. This study revealed that Kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)chromen-4-one) and Chymopain (disodium;4,5-dihydroxybenzene-1,3-disulfonate), natural flavonols present in Carica papaya and Gossypetin (3, 5, 7, 8, 3′, 4′-hexahydroxyflavone), a natural flavonoid available in Hibiscus sabdariffa were demonstrated promising good binding potential with minimum binding energy (kcal/mol) and maximum stabilizing interactions to the putative drug targets of CHIKV and DENV. The selected lead molecules demonstrated ideal drug likeliness, ADMET (adsorption, distribution, excretion, metabolism and toxicity) features required for the drug development. The molecular docking studies suggested that the presence of these compounds probably responsible for the antiviral properties of Carica papaya, which was traditionally known as therapeutic remedy for dengue viral infections. This study provides profound insight for the experimental validation of the applied approach and industrial scale-up of the suggested herbal lead molecules as promising lead candidates against CHIKV and DENV infections.

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Fig. 1

(Source: KEGG pathway database)

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References

  • Abu Bakar F, Ng LFP (2018) Nonstructural proteins of alphavirus-potential targets for drug development. Viruses. https://doi.org/10.3390/v10020071

    Article  PubMed  PubMed Central  Google Scholar 

  • Ajay A, Walters P, Murcko A (1998) Can we learn to distinguish between “drug-like” and “nondrug-like” molecules? J Med Chem 41:3314–3324

    Article  CAS  PubMed  Google Scholar 

  • Ajay A, Bemis W, Murcko A (1999) Blood brain barrier: designing libraries with CNS activity. J Med Chem 42:4942–4951

    Article  CAS  PubMed  Google Scholar 

  • Al-Tawfiq JA, Memish ZA (2018) Dengue Hemorrhagic Fever Virus in Saudi Arabia: A Review. Vector Borne Zoonotic Dis 18:75–81

    Article  PubMed  Google Scholar 

  • Ames BN, Gold SL (2000) Paracelsus to parascience: The environmental cancer distraction. Mutat Res 447:3–33

    Article  CAS  PubMed  Google Scholar 

  • Ashour J, Laurent-Rolle M, Shi PY, García-Sastre A (2009) NS5 of dengue virus mediates STAT2 binding and degradation. J Virol 83:5408–5418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bowie A (2010) TRAF3: Uncovering the Real but Restricted Role in Human. Immunity 33:293–295

    Article  CAS  PubMed  Google Scholar 

  • Bruno C (2011) Antiviral research and development against dengue Virus, WHO Rep, pp 1–101

  • Byler K, Collins J, Ogungbe I, Setzer W (2016) Alphavirus protease inhibitors from natural sources: a homology modeling and molecular docking investigation. Comput Biol Chem 64:163–184

    Article  CAS  PubMed  Google Scholar 

  • Carrillo-Hernández MY, Ruiz-Saenz J, Villamizar LJ, Gómez-Rangel SY, Martínez-Gutierrez M (2018) Co-circulation and simultaneous co-infection of dengue, chikungunya, and zika viruses in patients with febrile syndrome at the Colombian-Venezuelan border. BMC Infect Dis. 18(1): 61. https://doi.org/10.1186/s12879-018-2976-1

    Article  PubMed  PubMed Central  Google Scholar 

  • Colovos C, Yeates T (1993) Verification of protein structures: Patterns of nonbonded atomic interactions. Protein Sci 2:1511–1519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dayaraj C (2014) Current status of dengue and chikungunya in India. Seajph Jour 3:22–27

    Google Scholar 

  • Dhama K, Karthik K, Khandia R, Munjal A, Tiwari R, Rana R, Khurana SK, Khan RU, Alagawany M, Farag MR, Dadar M, Joshi SK (2018) Medicinal and therapeutic potential of herbs and plant metabolites / extracts countering viral pathogens—current knowledge and future prospects. Curr Drug Metab. https://doi.org/10.2174/1389200219666180129145252

    Article  PubMed  Google Scholar 

  • Fiser A, Sali A (2003) Modeller: Generation and refinement of homology-based protein structure models. Methods Enzymol 374:461–491

    Article  CAS  PubMed  Google Scholar 

  • Frimurer T, Bywater R, Nærum L, Lauritsen L, Brunak S (2000) Improving the odds in discriminating “drug-like” from “non drug-like” compounds. J Chem Inform Comput Sci 40:1315–1324

    Article  CAS  Google Scholar 

  • Gómez-Calderón C, Mesa-Castro C, Robledo S, Gómez S, Bolivar-Avila S, Diaz-Castillo F, Martínez-Gutierrez M (2017) Antiviral effect of compounds derived from the seeds of Mammea americana and Tabernaemontana cymosa on dengue and chikungunya virus infections. BMC Complement Altern Med 17:57. https://doi.org/10.1186/s12906-017-1562-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Irvine D, Takahashi L, Lockhart K, Cheong J, Tolan W, Selick E, Grove R (1999) MDCK (Madin-Darby canine kidney) cells: a tool for membrane permiability screening. J Pharm Sci 88:28–33

    Article  CAS  PubMed  Google Scholar 

  • Kawai T, Akira S (2008) Toll-like receptor and RIG-1-like receptor signaling. Ann N Y Acad Sci 1143:1–20

    Article  CAS  PubMed  Google Scholar 

  • Khan AH, Morita K, Parquet Md Mdel C, Hasebe F, Mathenge EG, Igarashi A (2002).Complete nucleotide sequence of chikungunya virus and evidence for an internal polyadenylation site. J Gen Virol 83(Pt 12):3075–3084

    Article  CAS  PubMed  Google Scholar 

  • Laskowski A, MacArthur W, Moss D, Thornton M (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Cryst 26:283–291

    Article  CAS  Google Scholar 

  • Laurie AT, Jackson RM (2005) Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites. Bioinformatics 21:1908–1916

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Siripanyaphinyo U, Tumkosit U, Noranate N, Atchareeya A, Pan Y, Kameoka M, Kurosu T, Ikuta K, Takeda N, Ananrapreecha S (2012) Poly (I:C), an agonist of toll-like receptor-3, inhibits replication of the Chikungunya virus in BEAS-2B cells. Virol J 9:114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lipinski C, Lombardo F, Dominy B, Feeney P (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv 46:3–26

    Article  CAS  Google Scholar 

  • Luis K, Shaohong L, Gabriel M, Ricardo J, Soares M, Archie C, Wenbiao H, Patricia B, Francesca F, Rebecca D, Laith Y (2016) Co-distribution and co-infection of chikungunya and dengue viruses, Furuya-Kanamori. BMC Infect Dis 16–84

  • Ma L, Jones CT, Groesch TD, Kuhn RJ, Post CB (2004) Solution structure of dengue virus capsid protein reveals another fold. Proc Natl Acad Sci USA 101:3414–3419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meyer E (1991) The first years of the protein data bank. Protein Sci 6:1591–1597

    Article  Google Scholar 

  • Moore C, Bergstralh D, Duncan A, Lei Y, Morrison E, Zimmermann G, Accavitti-Loper A, Madden J, Sun L, Ye Z, Lich D, Heise T, Chen Z, Ting P (2008) Nlrx1 is a regulator of mitochondrial antiviral immunity. Nature 451:573–577

    Article  CAS  PubMed  Google Scholar 

  • Mortelmans K, Zeiger E (2000) The Ames Salmonella/microsome mutagenicity assay. Mutat Res 2:29–60

    Article  Google Scholar 

  • O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR (2011) Open babel: an open chemical toolbox. J Cheminform 3:33. https://doi.org/10.1186/1758-2946-3-33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paymen N, Pierre G, Ahmet C, John H (2009) RIG-I-like receptors: Sensing and responding to RNA virus infection. Semin Immunol 21: 215–222

    Article  CAS  Google Scholar 

  • Perera-Lecoin M, Luplertlop N, Surasombatpattana P, Liegeois F, Hamel R, Thongrungkiat S, Vargas M, Yssel H, Misse D (2016) Dengue and chikungunya coinfection—the emergence of an underestimated threat. In: Rodriguez-Morale s AJ (ed) Current topics in chikungunya. Chap. 5, InTech, Rijeka, Croatia

  • Powers A (2015) Chikungunya virus outbreak expansion and micro evolutionary events affecting epidemiology and epidemic potential. Res Rep Trop Med 6:11–19

    Article  Google Scholar 

  • Powers CN, Setzer WN (2016). In in-silico investigation of phytochemicals as antiviral agents against dengue fever. Comb Chem High Throughput Screen 19: 516–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puerta-Guardo H, Glasner DR, Harris E (2016) Dengue Virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability. PLoS Pathog 12:e1005738. https://doi.org/10.1371/journal.ppat.1005738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramakrishnan C, Kutumbarao N, Suhitha S, Velmurugan D (2017) Structure-function relationship of Chikungunya nsP2 protease: a comparative study with papain. Chem Biol Drug Des 89:772–782

    Article  CAS  PubMed  Google Scholar 

  • Rashad A, Mahalingam S, Keller A (2014) Chikungunya virus: emerging targets and new opportunities for medicinal chemistry. J Med Chem 57:1147–1166

    Article  CAS  PubMed  Google Scholar 

  • Ruwali P, Rai N, Kumar N, Gautam P (2013) Antiviral potential of medicinal plants: an overview. Int Res J Pharm 4:8–16

    Article  Google Scholar 

  • Santhanam V, Waheeta H (2017) Towards the identification of novel phytochemical leads as macrodomain inhibitors of chikungunya virus using molecular docking approach. J Appl Pharm Sci 7:074–082

    Google Scholar 

  • Seeliger D, de Groot B (2010) Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J Comput Aided Mol Des 24:417–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seyedi S, Shukri M, Hassandarvish P, Oo A, Shankar E, Abubakar S, Zandi K (2016) Computational approach towards exploring potential anti-chikungunya activity of selected flavonoids. Sci Rep 6:1–7

    Article  CAS  Google Scholar 

  • Soe HJ, Yong YK, Al-Obaidi MMJ, Raju CS, Gudimella R, Manikam R, Sekaran SD (2018) Identifying protein biomarkers in predicting disease severity of dengue virus infection using immune-related protein microarray. Medicine (Baltimore) 97(5):e9713. https://doi.org/10.1097/MD.0000000000009713

    Article  CAS  Google Scholar 

  • Tan WL, Lee YK, Ho YF, Yusof R, Abdul Rahman N, Karsani SA (2018) Comparative proteomics reveals that YK51, a 4-Hydroxypandurantin-A analogue, down regulates the expression of proteins associated with dengue virus infection. PeerJ 5:e3939. https://doi.org/10.7717/peerj.3939

    Article  PubMed  PubMed Central  Google Scholar 

  • Thompson J, Gibson T, Hiqquins D (2002) Multiple sequence alignment using ClustalW and ClustalX. Curr Protoc Bioinform Chap 2:Unit 2.3. https://doi.org/10.1002/0471250953.bi0203s00

  • Torsten S, Jurgen K, Nicolas G, Manuel P (2003) SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Res 31:3381–3385

    Article  Google Scholar 

  • Trott O, Olson AJ (2010) AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem 31:455–461

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vázquez-Calvo Á, Jiménez de Oya N, Martín-Acebes MA, Garcia-Moruno E, Saiz JC (2017) Antiviral properties of the natural polyphenols delphinidin and epigallocatechin gallate against the flaviviruses West Nile virus, Zika virus, and Dengue virus. Front Microbiol 8:1314. https://doi.org/10.3389/fmicb.2017.01314

    Article  PubMed  PubMed Central  Google Scholar 

  • Veber F, Johnson R, Chen HY, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623

    Article  CAS  PubMed  Google Scholar 

  • Wiederstein J, Sippl M (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 35:W407–W410

    Article  PubMed  PubMed Central  Google Scholar 

  • Xie X, Zou J, Puttikhunt C, Yuan Z, Shi PY (2015) Two distinct sets of NS2A molecules are responsible for dengue virus RNA synthesis and virion assembly. J Virol 89:1298–1313

    Article  CAS  PubMed  Google Scholar 

  • Xu D, Zhang Y (2011) Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization. Biophys J 101:2525–2534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yazdanian M, Glynn L, Wright L, Hawi (1998) Correlating partitioning and Caco-2 cell permeability of structurally diverse small molecular weight compounds”. Pharm Res 15:1490–1494

    Article  CAS  PubMed  Google Scholar 

  • Yoneyama M, Fujita T (2009) RNA recognition and signal transduction by RIG-I-like receptors. Immunol Rev 227:54–65

    Article  CAS  PubMed  Google Scholar 

  • Zhong B, Yang Y, Li S, Wang Y, Li Y, Diao F, Lei C, He X, Zhang L, Tien P, Shu H (2008) The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29:538–550

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biotechnology, Dayananda Sagar College of Engineering, Bangalore, Karnataka, India

    Ambika R. Keramagi & Sinosh Skariyachan

  2. Visvesvaraya Technological University, Belagavi, India

    Sinosh Skariyachan

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  1. Ambika R. Keramagi
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  2. Sinosh Skariyachan
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Correspondence to Sinosh Skariyachan.

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Keramagi, A.R., Skariyachan, S. Prediction of binding potential of natural leads against the prioritized drug targets of chikungunya and dengue viruses by computational screening. 3 Biotech 8, 274 (2018). https://doi.org/10.1007/s13205-018-1303-2

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