• Users Online: 588
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

Table of Contents
Year : 2019  |  Volume : 56  |  Issue : 2  |  Page : 111-121

Isovaleric acid and avicequinone-C are Chikungunya virus resistance principles in Glycosmis pentaphylla (Retz.) Correa

1 Centre for Plant Biotechnology and Molecular Biology, College of Horticulture, Kerala Agricultural University, Thrissur, Kerala, India
2 Centre for Plant Biotechnology and Molecular Biology; Distributed Information Centre (Department of Biotechnology), College of Horticulture, Kerala Agricultural University, Thrissur, Kerala, India
3 Distributed Information Centre (Department of Biotechnology), College of Horticulture, Kerala Agricultural University, Thrissur, Kerala, India
4 Department of Plant Pathology, College of Horticulture, Kerala Agricultural University, Thrissur, Kerala, India

Date of Submission21-Nov-2017
Date of Acceptance15-Nov-2018
Date of Web Publication31-Jul-2019

Correspondence Address:
Deepu Mathew
Centre for Plant Biotechnology and Molecular Biology, Kerala Agricultural University, Thrissur, Kerala
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-9062.263719

Rights and Permissions

Background & objectives: Oral administration of tender leaf extract of Glycosmis pentaphylla is traditionally known to prevent the chikungunya virus infection. Even with wide usage, the antiviral components in this plant are neither identified nor characterized. This study was carried out with the objectives of profiling the phytocompounds in this plant through LC-MS/MS and to identify the active antiviral constituents and their drug-likeliness through molecular docking.
Methods: Phytocompounds were extracted hydro-alcoholically from powdered plant parts and analyzed using LC-MS/MS. Based on mass-to-charge ratio from LC-MS/MS, compounds were identified and used as ligands for molecular docking against chikungunya target proteins. The active principles were subjected to ADME/T analysis to verify their drug-likeliness.
Results: The docking results and ADME/T evaluation showed that the compounds, isovaleric acid and avicequinone- C have good interaction with the protein targets and hence could be the antiviral principles of the selected plant. These compounds presented acceptable drug properties and hence could be carried forward to in vivo studies for drug development.
Interpretation & conclusion: The antiviral properties of G. pentaphylla are known since time-immemorial. This study revealed the probable interactions after the oral administration of tender leaves of Glycosmis in preventing the chikungunya virus infection and paves the path for designing future plant-based drugs.

Keywords: ADME/T; drug development; herbal medicine; in silico; LC-MS/MS; molecular docking

How to cite this article:
Brinda O P, Mathew D, Shylaja M R, Davis P S, Cherian K A, Valsala P A. Isovaleric acid and avicequinone-C are Chikungunya virus resistance principles in Glycosmis pentaphylla (Retz.) Correa. J Vector Borne Dis 2019;56:111-21

How to cite this URL:
Brinda O P, Mathew D, Shylaja M R, Davis P S, Cherian K A, Valsala P A. Isovaleric acid and avicequinone-C are Chikungunya virus resistance principles in Glycosmis pentaphylla (Retz.) Correa. J Vector Borne Dis [serial online] 2019 [cited 2023 Mar 28];56:111-21. Available from: http://www.jvbd.org//text.asp?2019/56/2/111/263719

  Introduction Top

Since time-immemorial, human kind has been remained dependent on plants for their medicinal effects and today, the demand is on the rise due to the presumed lesser side-effects. Secondary metabolites, which are not directly involved in growth, development and reproduction of plants, are the key elements for medicinal properties of plants. The traditional medicinal systems such as Ayurveda work through combining several phytocompounds in suitable proportions. Orange berry [Glycosmis pentaphylla (Retz.) Correa], distributed in the Western Ghats (India) and throughout the tropical humid climates of the world, is used in Ayurveda for cough, rheumatism, anaemia, cancer and jaundice. The tender leaf infusion of the plant is orally administered as a preventive strategy against chikungu-nya virus (CHIKV). The antifungal[1] activities of this plant have been scientifically explained. Further, the medicinal properties including the antioxidant effects of berries owing to their free-radical seeking properties[2], apoptosis inducing effects on liver cancer cells[2], inhibitory effects on Down Syndrome through the suppression of DYRK1A key proteins by acridone alkaloids[3] and many others have also been scientifically demonstrated. Even with the extensive use of this plant for its antiviral properties, there is no scientific validation on the active compounds involved and their modes of action. No drugs have been developed so far, against the CHIKV; hence, detailed insight on the molecules involved, and the mode of interactions can lead to the development of potential drug candidates.

Chikungunya virus is a mosquito-borne alphavirus (Family: Togaviridae)[4] Several compounds such as, prostratin and 12-O-tetradecanoylphorbol 13-acetate from Trigonostemon howii[5], jatrophane diterpenes from Euphorbia amygdaloides sp. semiperfoliata[6], tigliane diterpenes from Croton mauritiamus[7], and trigocherrierin from Trigonstemon cherrieri have been reported to inhibit CHIKV replication. However, the reports on further work on these molecules, leading to the development of drug are not available.

Extraction of active ingredients followed by liquid chromatography-tandem mass spectrometry (LC-MS/ MS) analysis and in silico docking is the accepted strategy for drug discovery[9]. Molecular docking facilitates the screening of large number of phytocompounds for their capability to interact with and deactivate the viral proteins or infection induced proteins in human body and is an effective strategy in drug discovery. This study was aimed to characterize the active ingredients in G. pentaphylla through LC-MS/MS and to identify the antiviral compounds against chikungunya through molecular docking.

  Material & Methods Top

Plant material

The whole plants of G. pentaphylla were collected from it natural habitat in Kerala state, India (10.85° N, 76.27° E). Leaves were cleaned with distilled water, shade-and oven-dried at 40 °C, and milled into fine powder. The leaf powder was subsequently used for hydro-alcoholic extraction (90 : 10) of phytocompounds.

Extraction and identification of phytocompounds

Hydroalcoholic extraction of phytochemicals was done by percolation at room temperature followed by filtration using the standard protocols[10]. The extract was maintained in a conical flask tightly plugged with cotton [Figure 1] and concentrated using hot water bath. Samples were analysed by LC-MS/MS analysis in UPLC machine (Waters Acquity, Milford, USA) with triple quadrupole mass spectrometer. Crude extract (5 ppm) was infused using acetonitrile and water in the ratio 1 : 1 and formic acid. Electro spray ionization with a positive mode polarity (ES+) was given at 3300 V capacity voltage, 35 V cone voltage, 8 L/min gas flow rate, 150 °C source temperature and 500 °C desolution temperature.
Figure 1: Hydroalcoholic extract from: (a) leaf, and (b) root of G. pentaphylla, used in the LC-MS/MS analysis.

Click here to view

In silico docking studies for antiviral properties

The phytocompounds extracted from the leaves of G. pentaphylla were used in the molecular docking studies. Three dimensional structures of these compounds were retrieved from PubChem database (https://pub-chem.ncbi.nlm.nih.gov/) in .sdf format[11]. The protein targets were identified from the chikungunya drug target database (CDTD, http://www.biocdtd.org/). Three-dimensional X-ray crystallographic structures were downloaded from the Protein Data Bank (http://www.rcsb.org/ pdb/home/home.do), and used to dock with the identified phytocompounds.

Preparation of ligands and their filtration

Software discovery studio (DS), version 4.0 was used in the molecular docking studies. Preparation of the retrieved structures of ligands was done using ‘Prepare ligand’ protocol in DS, which removed duplicates, enumerated tautomers/ isomers, added hydrogen bonds and minimized energy using CHARMm (Chemistry at Harvard Macromolecular Mechanics) force field[12]. The prepared ligands were filtered by Lipinski’s Rule of five (Ro5) and Vebers’ protocol (VP) that defines the criteria for drug-likeness and focuses on drugs’ bioavailabil- ity[13],[14]. The Ro5 and VP were used to screen the compounds on the basis of molecular weight (MW, ≤500 daltons), number of hydrogen bond donors (HBD, ≤5) and hydrogen bond acceptors (HBA, ≤10), number of rotatable bonds (RB, ≤10), logP value (≤5) and polar surface area (PSA, ≤140 Å2). The filtered ligands were then forwarded for molecular docking with chikungunya target proteins.

Preparation of protein molecules and active site identification

A total of 12 protein targets for chikungunya disease, reported in CDTD were used in the study. The 3D structures were downloaded from PDB [Figure 2]. Of the 12 proteins, five were viral proteins viz. immature glycoprotein complex, mature envelope glycoprotein complex, macrodomain protein of CHIKV, nsp3 macrodomain and chikungunya nsp2 protease. The other proteins included, heat shock protein 70 kDa (HSP 70), interleukin 6 (IL- 6), tumour necrosis factor a (TNF-α), interferon ß, signal transducer and activator protein, human leukocyte antigen and actin. The ‘Prepare protein’ protocol of DS corrected the protein structures by inserting missing at-oms, adding hydrogen atoms, modelling loop regions and side chains, removing water molecules, natural ligands and heteroatoms and minimizing the energy to achieve stable conformation by using CHARMm force field. The active sites were selected using the current selection option of DS. Including the selected active site and critical functional residues present in the protein, a grid receptor sphere was generated [Figure 3].
Figure 2: X-ray crystallographic 3D structure of 12 target proteins retrieved from PDB: (a) Immature glycoprotein complex of chikungunya virus (PDB ID 3N40); (b) Mature envelope glycoprotein complex of chikungunya virus (PDB ID: 3N44); (c) Macrodomain of chikungunya virus (PDB ID: 3GPO);(d) Chikungunya virus nsp3 macrodomain (PDB ID: 4TUO); (e) Chikungunya nsp2 protease (PDB ID: 3TRK); (f) Heat shock 70 kDa protein (PDB ID: 3DOB); (g) Inter- leukin-6 (PDB ID: 1ALU); (h) Tumour necrosis factor alpha (PDB ID: 3KMC); (i) Interferon beta (PDB ID: 1AU1); (j) Signal transducer and activator protein (PDB ID: 3ZMM); (k) Human leukocyte antigen (PDB ID: 2G9H); and (l) Actin protein (PDB ID: 4M63).

Click here to view
Figure 3: Model for grid-based selection of bind site in a ligand-target protein docking using Discovery Studio ver. 4.0.

Click here to view

Molecular interaction and binding

Molecular docking was performed between the structures of prepared chikungunya target proteins and those of phytocompounds by ‘CDOCKER’ protocol of DS[15] The pose which contained the least difference between CDOCKER energy and CDOCKER interaction energy was considered as best interaction, along with the lowest binding energy calculation as the scoring function. Number of hydrogen bonds between the targets and the ligands were also recorded.

Pharmacokinetic evaluation

The in silico tool ‘ADMET descriptors’ in DS was used to evaluate the pharmacokinetic parameters and to assess the quality of the molecule in terms of absorption, distribution, metabolism, excretion and toxicity after human ingestion[16]. This technique reduces the cost and chance of clinical failures of new drugs. The parameters calculated by this descriptor included human intestinal absorption, aqueous solubility, blood brain barrier (BBB), hepato-toxicity, CYP2D6 inhibition and plasma protein binding (PPB)[17].

Ethical statement: Not applicable.

  Results Top

LC-MS/MS analysis yielded the chromatographic peaks representing the mass of the phytocompounds [Figure 4]. The peaks represented the relative abundance of individual molecules in the extract. Based on the standard protocol, using the mass to charge ratio of the molecules, 23 phytocompounds were identified from the library and used in the molecular docking studies [Table 1]. The prepared ligands were filtered on the basis of Lipinski’s and Veber’s rule. All the ligands, except myricyl alcohol, passed these rules [Table 2] and were subjected for further docking.
Table 1: Phytocompounds selected as ligands in molecular docking studies

Click here to view
Table 2: Screening of phytocompounds from leaves of Glycosmis pentaphylla using Lipinski’s and Veber’s rule

Click here to view
Figure 4: LC-MS/MS chromatogram showing the molecular weight of the phytocompounds from leaf extract.

Click here to view

The binding sites for the receptor proteins were selected from the software on the basis of PDB site recorder. Molecular docking was performed for the targets identified for chikungunya virus with the selected ligands. A total of 10 poses were allowed to be obtained for each interacting molecules. The scoring function was analysed among the molecules using CDOCKER energy, CDOCKER interaction energy and binding energy calculation. Hydrogen bond formation among the targets and ligands were also recorded. The docked poses for each of the compounds were evaluated [Table 3] and the pose with lowest binding energy was considered as the best interaction [Table 4].
Table 3: Dock scores for the interaction of phytocompounds with chikungunya target proteins

Click here to view
Table 4: Dock score in molecular interaction between selected targets and phytocompounds

Click here to view

Dock scores for immature glycoprotein complex showed that the interaction energy for isovaleric acid and avicequinone-C had minimum difference between the CDOCKER energy and CDOCKER interaction energy [Table 4]. Isovaleric acid bound to the protein (bond distance –2.093 Å) with a binding energy of –92.909 kcal/ mol. Hydrogen bond formed during this interaction was found to involve the Lys219 amino acid residue. Avice- quinone-C interaction with the target immature glyco-protein complex had a binding energy of -50.803 kcal/ mol (bond distance -1.873 Å). A single hydrogen bond involving Lys219 was generated in this interaction. Out of 22 ligands used for docking, only 21 ligands showed interaction. Among these hydrogen bonds and binding energy was obtained only for isovaleric acid and avice- quinone-C.

Mature envelope glycoprotein of chikungunya had interacted with 11 compounds [Table 3]. Among these compounds, only isovaleric acid and avicequinone-C displayed favourable levels of interaction. Isovaleric acid displayed a binding energy of -144.111 kcal/mol. This interaction resulted in a hydrogen bond of 2.072 Å with the involvement ofAsn231 as critical amino acid residue. Avicequinone-C interaction showed a comparatively lower binding energy (-44.211 kcal/mol). But this interaction also yielded two bonds with bond distances of 1.912 and 1.757 Å, where critical amino acid residues involved were His232 and Lys233, respectively.

Docking the ligands from leaf extract with the macrodomain of chikungunya virus had yielded satisfactory interaction by 22 molecules [Table 3]. Isovaleric acid formed three hydrogen bonds with this protein, involving amino acid residues Thr111, Gly 112 and Tyr114. The binding energy obtained from this interaction was -169.101 kcal/mol and the hydrogen bond distances were 2.377, 2.078 and 2.090Å, respectively. Avicequinone-C formed two hydrogen bonds involving the amino acids Val33 and Ser110 with bond distances of 2.146 A° and 2.299 Å, respectively.

Of the 21 ligands that interacted with CHIKV nsp3 macrodomain protein, interaction was best for isovaleric acid with binding energy of –154.301 kcal/mol forming two hydrogen bonds at bond distances of 2.329 and 2.043 Å [Table 4]. Avicequinone-C formed three hydrogen bonds with binding energy of -76.983 kcal/mol. Amino acids involved were Val35, Ser112 and Thr113 and the hydrogen bond distances were 1.976, 2.344 and 2.278 Å, respectively.

Among 18 interacting phytocompounds with inter-leukin IL-6, only two compounds were rated with good dock score values. Isovaleric acid formed three hydrogen bonds at 2.491, 2.024 and 1.932 Å [Table 4]. In all these bonds, amino acid involved was Arg179 and the binding energy was -141.095 kcal/mol. Avicequinone-C interacted with the protein forming a single hydrogen bond (bond distance of 1.754 Å). The protein targets selected for the study, TNFa, nsp2 protease and HSP-70 showed no interaction with phytocompounds from the leaf extract of Glycosmis pentaphylla [Table 3].

Both isovaleric acid and avicequinone-C interacted well with the interferon ß protein but interaction by isovaleric acid was better, with bond distance of 2.279 Å. Ser[12] was the amino acid involved and binding energy was – 61.483 kcal/mol. When signal transducer and activator of transcription II proteins were docked, 18 compounds interacted but only avicequinone-C formed a hydrogen bond through Arg980 at 1.889 Å distance. Among the 19 leaf compounds that reacted with human leukocyte antigen, only avicequinone-C showed satisfactory interaction. Amino acid His167 was involved in the hydrogen bond formation with a bond distance of 2.393 Å and binding energy of –48.604 kcal/mol. With the actin, 21 ligands reacted but only isovaleric acid and avicequinone- C had satisfactory interaction. Isovaleric acid formed two hydrogen bonds through Lys18 with the bond distances of 2.147 and 1.912 Å and binding energy of –170.727 kcal/mol. Avicequinone-C formed two hydrogen bonds through Tyr306 and Lys336 at 2.167 and 1.724 Å distance.

ADME/T properties of the G. pentaphylla compounds which interacted with all the chikungunya targets are summarized in [Table 5]. The ADME/T properties of isovaleric acid and avicequinone-C were critically assessed and most of the scores were within the optimum level, except two parameters. Even with that they had acceptable level for bioavailability, showing that these compounds are suitable for developing antiviral drugs against chikungunya.
Table 5: ADME/T properties of phytocompounds from G. pentaphylla leaf sample

Click here to view

  Discussion Top

Various classes of compounds viz. terpenoids, amides, coumarins and flavonoids[18] have been reported from Glycosmis pentaphylla. The phytochemicals identified include arborinine, glycozolicine, 3-formyl car-bazole, glycosinine, mupamine, varbazole, 3-methyl carbazole, glycolone, glycozolidol, glycozolinine, gly-cophymoline, glycophymine, glycomide, glycozoline, noracronycine, des-N-methyl acronycine and des-N-methyl noracronycine[19]. Air-dried leaves of Glycosmis contain two furoquinoline bases, kokusaginine and skim-mianine; additionally, glycophymoline, glycophymine, glycomide, glycozoline, noracronycine, des-N-methyl acrocynine and des-N-methyl noracronycine have been reported from this plant[2]. Other alkaloids reported from the leaves include glycosine, arborine, glycosminine, ar-borinine (major), glycosamine glycorine, glycosmicine, γ-fagarine triterpenes, arbinol and isoarbinol, arbori-none, two isomeric terpene alcohols, myricyl alcohol, stigmasterol and ß-sitosterol[18]. However, none of these compounds have been screened and reported for their antiviral properties.

The genome of CHIKV consists positive sense, single-stranded RNA. There are two open reading frames (ORFs), at the 5’-end encoding the non-structural protein precursors: nsP1 helps in viral mRNA capping via its guanine-7-methyltransferase and guany[1] transferase enzymatic activities[20], nsp2 protease acts as protease and helicase, nsp3 is part of the replicase unit and an accessory protein involved in RNA synthesis, and nsp4 is RNA-dependent-RNA polymerase[21]. For the synthesis of viral negative strand, the nsp1-2-3 precursors and nsp4 functions as a complex. The ORF at the 3’-end encodes the structural proteins, the capsid (C), envelope glycoproteins E1 and E2 and two small cleavage products (E3, 6K). These proteins, play significant role during the essential steps in the lifecycle of the virus, and hence, considered as possible targets for drug design.

Of the candidate proteins selected, HSP-70 is reported to assist the CHIKV in mammalian cell entry by acting as a binding protein[22] During chikungunya infection, the inflammatory response of the protein, IL-6 mediates the virus. The activation of viral infection is associated with increased expression levels of another protein, TNF-α. It helps in induction of apoptosis in cells. The protein interferon-ß is released by host cells as an immune response trigger during viral infection. Following the viral infection with enhanced expression, these interferons are expressed by fibroblasts[23]. The CHIKV utilises signal transducer and activator of transcription 2 (STAT2) to facilitate infection in mammals[24].

Isovaleric acid and avicequinone-C have shown satisfactory interaction with chikungunya envelope glycoprotein complex which have important role in viral entry into the cells. Lys279 residue in immature glycoprotein complex was found to interact with both of these molecules. Asn231 residue in mature glycoprotein complex interacted with isovaleric acid whereas His232 and Lys233 were the residues interacting with avicequinone-C. A recent conformational sampling through docking has reported Gly91 and His230 in chikungunya glycoprotein complex as the key residues in fusion function[25].

The study established that two molecules, isovaleric acid and avicequinone-C are the antiviral agents in G. pentaphylla. The isovaleric acid is reported to induce profound effects on mammalian systems, including the alteration in key enzyme activities[26] Valeric acid was previously identified to have antiviral properties and was used in the formulation of a virucidal ointment for prevention of transmission and contraction of common colds[27]. Similarly, valeric acid derived o-hexylphenoxy acetic acid was also demonstrated to have antiviral activity against Japanese B encephalitis virus[28]. Avicequinone- C extracted from Avicennia leaves is reported to have hepato-protective action and activity against the toxic agents[29]. Though, an earlier molecular docking study has shown that molecules including the avicequinone-C from mangroves hold high level therapeutic potential due to its capability to interact with a wide spectrum of disease related proteins[30], the antiviral property of this molecule has not been shown so far. The study findings revealed the antiviral activity of avicequinone-C and explained the mode of interaction of the molecules.

  Conclusion Top

Traditional system use G. pentaphylla to treat the chikungunya disease. This study, designed to understand the molecular mechanism of antiviral property of this plant through molecular docking of its active ingredients, indicates that isovaleric acid and avicequinone-C molecules are capable to interact with the chikungunya causing proteins. ADME/T profiling of the phytocompounds revealed that these two compounds are promising molecules for proceeding into drug development against chikungunya virus.

Conflict of interest

The authors declare that they do not have any financial or commercial interest vested with this study.

  Acknowledgements Top

The authors acknowledge the financial support for this project by the Department of Biotechnology, Ministry of Science and Technology, Govt. of India.

  References Top

Greger H, Zechner G, Hofer O, Hadacek F, Wurz G. Sulphur-containing amides from Glycosmis species with different antifungal activity. Phytochemistry 1993; 34(1): 175-9. doi: 10.1016/S0031-9422(00)90802-1.  Back to cited text no. 1
Sreejith PS, Praseeja RJ, Asha VV. A review on the pharmacology and phytochemistry of traditional medicinal plant, Glycosmis pentaphylla (Retz.) Correa. J Pharm Res 2012; 5(5): 2723-8.  Back to cited text no. 2
Beniddir MA, Le Borgne E, Iorga BI, Loaëc N, Lozach O, Meijer L, et al. Acridone alkaloids from Glycosmis chlorosper-ma as DYRK1A inhibitors. J Nat Prod 2014; 77(5):1117-22. doi: 10.1021/np400856h.  Back to cited text no. 3
Leyssen P, Smadja J, Rasoanaivo P, Gurib-Fakim A, Maho-moodally MF, Canard B, et al. Biodiversity as a source of potent and selective inhibitors of chikungunya virus replication. In: Gurib-Fakim A, editor. Novel plant bioresources: Applications in food, medicine and cosmetics, I edn. Chichester, West Sussex: John Wiley & Sons Inc. 2014; p. 455.  Back to cited text no. 4
Bourjot M, Delang L, Nguyen VH, Neyts J, Guéritte F, Leyssen P, et al. Prostratin and 12-O-tetradecanoylphorbol 13-acetate are potent and selective inhibitor of chikungunya virus replication. J Nat Prod 2012; 75(12): 2183-7. doi: 10.1021/np300637t.  Back to cited text no. 5
Nothias-Scalgia LF, Retailleau P, Paolini J, Pannecouque C, Neyts J, Dumontet V, et al. Jatrophane diterpenes as inhibitors of chikungunya virus replication: Structure-activity relationship and discovery of a potent lead. J Nat Prod 2014; 77(6): 1505-12. doi: 10.1021/np5002Hu.  Back to cited text no. 6
Corlay N, Delang L, Girard-Valenciennes E, Neyts J, Clerc P, Smadja J, et al. Tigliane diterpenes from Croton mauritianus as inhibitor of chikungunya virus replication. Fitoterapia 2014; 97: 87-91. doi: 10.1016/j.fitote.2014.05.015.  Back to cited text no. 7
Bourjot M, Leyssen P, Neyts J, Dumontet V, Litaudon M. Trigocherrienrin a potent inhibitor of chikungunya virus replication. Molecules 2014; 19: 3617-27. doi: 10.3390/mole-cules190336H.  Back to cited text no. 8
Gaddaguti V, Mounika SJ, Sowjanya K, Rao T, Chakravar-thy MK, Allu R. GC-MS analysis and in silico molecular docking studies of mosquito repellent compounds from Hyp- tis suaveolens L. Int J Bioass 2012; 1: 36-41. doi: 10.2H46/ ijbio.2012.09.003.  Back to cited text no. 9
Kaneria M, Kanani B, Chanda S. Assessment of effect of hy-droalcoholic and decoction methods on extraction of anti- oxidants from selected Indian medicinal plants. Asian Pac J Trop Biomed 2012; 2(3): 195-202. doi: 10.1016/S2221- 1691(12)60041-0.  Back to cited text no. 10
Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, et al. PubChem substance and compound databases. Nucleic Acids Res 2015; 44(D1): D1202-13. doi: 10.1093/nar/gkv951.  Back to cited text no. 11
Brooks BR, Brooks CL, Mackerell Jr AD, Nilsson L, Petrella RJ, Roux B, et al. CHARMm: The biomolecular simulation program. J Comput Chem 2009; 30(10):1545-614. doi: 10.1002/ jcc.21287.  Back to cited text no. 12
Lipinski CA. Lead-and drug-like compounds: The rule-of-five revolution. Drug Discov Today Technol 2004; 1(4): 331-41. doi: 10.1016/j.ddtec.2004.11.007.  Back to cited text no. 13
Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002; 45(12): 2615-23. doi: 10.1021/jm020017n.  Back to cited text no. 14
Wu G, Robertson DH, Brooks III CL, Veith M. Detailed analysis of grid-based molecular docking: A case study of CDOCKER-A CHARMm-based MD docking algorithm. J Comput Chem 2003; 24(13): 1549-62. doi: 10.1002/jcc.10306.  Back to cited text no. 15
Tian S, Wang J, Li Y, Li D, Xu L, Hou T. The application of in silico drug-likeness predictions in pharmaceutical research. Adv Drug Deliv Rev 2015; 86: 2-10. doi: 10.1016/j. addr.2015.01.009.  Back to cited text no. 16
H. Usha T, Goyal AK, Lubna S, Prashanth H, Mohan TM, Pande V, et al. Identification of anti-cancer targets of eco-friendly waste Punica granatum peel by dual reverse virtual screening and binding analysis. Asian Pac J Cancer Prev 2014; 15: 10345-50. doi: 7314/APJCP.2014.15.23.10345.  Back to cited text no. 17
Wu TS, Chang FC, Wu PL. Flavonoids, amidosulfoxides and an alkaloid from the leaves of Glycosmis citrifolia. Phytochemistry 1995; 39(6): 1453-7. doi: 10.1016/0031- 9422(95)00171-3.  Back to cited text no. 18
Sarkar M, Chakraborty DP. Glycophymoline, a new minor quin-azoline alkaloid from Glycosmis pentaphylla. Phytochemistry 1919; 18: 694-5.  Back to cited text no. 19
Solignat M, Gay B, Higgs S, Briant L, Devaux C. Replication cycle of chikungunya: A re-emerging arbovirus. Virol 2009; 393(2): 183-91. doi: 10.1016/j.virol.2009.01.024.  Back to cited text no. 20
Shirako Y, Strauss EG, Strauss JH. Suppressor mutations that allow Sindbis virus RNA polymerase to function with non-aromatic amino acids at the N-terminus: Evidence for interaction between nsp1 and nsp4 in minus-strand RNA synthesis. Virol 2000; 276(1): 148-60. doi: 10.1006/viro.2000.0544.  Back to cited text no. 21
Reddy V, Mani RS, Desai A, Ravi V. Correlation of plasma viral loads and presence of chikungunya IgM antibodies with cytokine/chemokine levels during acute chikungunya virus infection. J Med Virol 2014; 86(8): 1393-401. doi: 10.1002/ jmv.23875.  Back to cited text no. 22
Rudd PA, Wilson J, Gardner J, Larcher T, Babarit C, Le TT, et al. Interferon response factors 3 and 7 protect against chikun-gunya virus hemorrhagic fever and shock. J Virol 2012; 86(18): 9888-98. doi: 10.1128/JVI.00956-12.  Back to cited text no. 23
Paingankar MS, Arankalle VA. Identification of chikungunya virus interacting proteins in mammalian cells. J Biosci 2014; 39: 389-99. doi: 10.1007/s12038-014-9436-x.  Back to cited text no. 24
Nguyen PTV, Yu H, Keller PA. Molecular docking studies to explore potential binding pockets and inhibitors for Chikungunya virus envelope glycoproteins. Interdiscip Sci Comput Life Sci 20H; doi:10.1007/s12539-016-0209-0.  Back to cited text no. 25
Ribeiro CAJ, Balestro F, Grando V, Wajner M. Isovaleric acid reduces Na+, K+-ATPase activity in synaptic membranes from cerebral cortex of young rats. Cell Mol Neurobiol 2007; 27:529-40. doi: 10.1007/s10511-001-9143-3.  Back to cited text no. 26
21. New KC. Use of a virucidal ointment in the nares for prevention of transmission and contraction of common colds. U.S. Patent Application 11/845, 2001; p. 156.  Back to cited text no. 27
Ueda F, Ueda T, Toyoshima S. Researches on chemotherapeutic drugs against viruses XXIV. Studies on the syntheses and antiviral effect of 2-alkylphenoxyalkanoic acids. Chem Pharm Bull 1959; 7:829-33. doi: 10.1248/cpb7.829.  Back to cited text no. 28
Gholami M, Mirazi N. Study of hepato-protective effects of Avicennia marina hydro-ethanolic leaves extract in male rats induced with carbon tetrachloride. Yasuj University Med Sci J 2016; 20: 858-12.  Back to cited text no. 29
Devi AS, Joseph J, Rajkumar J. In silico drug designing approach to treat infectious disease using mangrove through docking analysis. J Environ Biol 2016; 37: 1401-6.  Back to cited text no. 30


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

This article has been cited by
1 Analysis of aromatic components of two edible mushrooms, Phlebopus portentosus and Cantharellus yunnanensisusing HS-SPME/GC-MS
Run Tian, Zhi-Qun Liang, Yong Wang, Nian-Kai Zeng
Results in Chemistry. 2022; : 100282
[Pubmed] | [DOI]
2 Methylgerambullin Derived From Plant Glyccsmis Pentaphylla (Retz) Correa. Mediates Anti-Hepatocellular Carcinoma Cancer Effect by Activating Mitochondrial and Endoplasmic Reticulum Stress Signaling and Inhibiting AKT and STAT3 Pathways
Chaoqun Wu,Guangwen Shu,Huiqi Huang,Kejian Pang,Xinzhou Yang,Guangzhong Yang
Food and Chemical Toxicology. 2021; : 112031
[Pubmed] | [DOI]
3 Traditional uses, phytochemistry, pharmacology, toxicology and formulation aspects of Glycosmis species: A systematic review
Parusu Kavya Teja,Prachi Patel,Drashti Bhavsar,Chintakindi Bindusri,Kishori Jadhav,Siddheshwar K. Chauthe
Phytochemistry. 2021; 190: 112865
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
Material & M...
Article Figures
Article Tables

 Article Access Statistics
    PDF Downloaded715    
    Comments [Add]    
    Cited by others 3    

Recommend this journal