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 Table of Contents  
Year : 2019  |  Volume : 9  |  Issue : 3  |  Page : 198-202

Biocomputational approaches towards deciphering anti-dengue viral properties of synthetic and natural moieties

1 Department of Biotechnology, NIPER-Ahmedabad, Gandhinagar, Gujarat, India
2 Department of Natural Products, NIPER-Ahmedabad, Gandhinagar, Gujarat, India
3 Department of Pharmacology, Karnavati School of Dentistry, Karnavati University, Gandhinagar, Gujarat, India

Date of Web Publication6-Sep-2019

Correspondence Address:
Neelam Chauhan
Department of Pharmacology, Karnavati School of Dentistry, Karnavati University, 907/A, Uvarsad, Gandhinagar - 382 422, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2321-8568.266224

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Introduction: Dengue, an arthropod-borne disease caused due to dengue virus belonging to Flaviviridae, is a serious health problem globally. Currently, there is no licensed vaccine for prophylaxis of the infection or an effective drug regimen for treatment. The virus genome codes for three structural and seven non-structural proteins. Envelope protein is required for the attachment and binding of the virus to the host cells, viral replication and hence, it can act as a good antiviral target. Method: We intend to evaluate the antiviral activity of compounds from both natural and synthetic sources by using tools of bioinformatics and computational biology. The favourable sites for drug binding, ligand interaction were analysed by various modules of Schrodinger software (2016-1). Results: Results indicated the amino acids – cysteine 3, arginine 2, threonine 155, tyrosine 132 and asparagine 194 show major interactions such as van der Waals and hydrophobic interaction with the different functional groups of the drug molecules. Conclusion: We observed the natural compounds such as rutin, gallic acid and ellagic acid showed better binding affinity in comparison to the synthetic antiviral drugs such as acyclovir, tenofovir and oseltamivir on different sites of the envelope protein suggesting the plausible anti-dengue viral property.

Keywords: Acyclovir, antiviral, computational, dengue, envelope, molecular docking, rutin

How to cite this article:
Powale K, Kamble B, Chauhan N. Biocomputational approaches towards deciphering anti-dengue viral properties of synthetic and natural moieties. Adv Hum Biol 2019;9:198-202

How to cite this URL:
Powale K, Kamble B, Chauhan N. Biocomputational approaches towards deciphering anti-dengue viral properties of synthetic and natural moieties. Adv Hum Biol [serial online] 2019 [cited 2021 Apr 17];9:198-202. Available from: https://www.aihbonline.com/text.asp?2019/9/3/198/266224

  Introduction Top

Dengue is a vector-borne, fast-emerging viral disease in various parts of the world flourishing in urban as well as rural areas majorly in tropical and subtropical countries. Annually >50–70 million cases are reported globally putting half the world population under the risk of this infection.[1] The dengue virus (DENV) is of four types transmitted to the humans via vector mainly Aedes aegypti or Aedes albopictus following the enzootic pathway. Dengue exacerbates as dengue fever or dengue haemorrhagic fever or in severe cases as dengue shock symptom. Currently, there is no licensed vaccine for prophylaxis or a drug regimen to treat or lessen the duration of the infection. The medication prescribed are for treatment of symptomatic indications.[2] Currently, significant efforts are being employed to identify drug candidates for treating the infection. There has been a constant effort towards deciphering and recognising novel targets and biomarkers present on the virus along with identifying effective molecules from both natural and synthetic sources.[3] In recent times, computational drug chemistry is proving to be an efficient tool for identification and prediction of compounds that can have anti-dengue activity.[4] Molecular docking is an important structural molecular biology and computer-assisted drug design method. It predicts structure of the intermolecular complex which is formed in-between two or more constituent molecules. The aim in protein ligand docking is to predict the binding model of a ligand with a protein of known structure. The central idea is to dock a large number of potential molecules into a protein's binding site and further rank them based on their calculated binding affinities and energies. Owing to an approximation of the simulations and calculated binding affinity of itself, it is used to identify protein cognate ligands among a huge number of candidates, and this approach can be useful to narrow down the number of molecules that need to be testedin vitro conditions.[5]

The dengue virion particle consists of lipoprotein envelope and an icosahedral-shaped nucleocapsid containing a positive single-stranded RNA genome. The RNA that codes for integral membrane proteins designated envelope (E) and premembrane (prM) and the seven structural proteins have been named as NS1, NS2a, NS2b, NS4a, NS4b and NS5.[6],[7] The envelope protein is glycosylated and arranged in homodimers on the viral surface. They are involved in receptor binding and entry into the susceptible or host cells. It facilitates receptor binding and fusion to the endosomal membrane during cell entry. The E protein consists of three domains: DI, DII and DIII. The tip of DII contains the fusion loop that directly interacts with the endosomal membrane during fusion.[8] The Domains I and II are connected with a flexible hinge that allows rotation of the Domain DII relative to DI–DIII during the processes of viral maturation and fusion of the viral envelope with the host cell membrane. These domains may, therefore, represent an ideal target for structure-based design of potential antiviral agents since ligands that bind them can alter the conformational equilibrium associated with the hinge angle and further inhibit virus maturation.[9]

There is search and an increasing requirement for substances with antiviral activity since most of the prescribed antiviral drugs attain viral resistance. Plant-based compounds are safer, non-toxic and relatively cheaper than the synthetic compounds. Hence, such compounds if found to possess antiviral property may prove to be an excellent alternative to the synthetic ones.[10] The objective of this study is to screen different class of compounds and to target them against the envelope protein of the DENV which may help to restrain the DENV infection. In an attempt to analyse and compare different compounds to have antiviral activity, we have docked molecules from both natural and synthetic sources on the envelope protein of the DENV. The result of this study shall provide meaningful information regarding drug development and further would prove beneficial in computer-assisted screening of the drugs against DENV infection.

  Materials and Methods Top

The computational studies were performed using Maestro (10.5) suite of Schrödinger version 2016-1, between the array of compounds and DENV 1 envelope protein.[11]


The Protein Data Bank (PDB) (www.rcsb.org) is a worldwide repository for distribution and processing of three-dimensional biological molecular structure data. The protein crystal structures of the structural envelope protein of DENV-1 of PDB ID 3G7T from PDB was employed for building the structure. The built structure was evaluated for its dihedral angles of its amino acids using Ramachandran Plot. The residues in favoured, allowed and outerlined regions were observed [Figure 1].
Figure 1: The Ramachandran plot for dengue virus envelope protein indicating 90% amino acids in the favoured region, 7% amino acids in allowed region and rest of the amino acids per cent in outer lined regions.

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The compounds selected from both natural and synthetic sources were considered as ligands. The compounds from natural sources belonged to the varied classes [Table 1] such as alkaloids, tannins and glycosides such as quercetin, gallic acid, ellagic acid, castanospermine, pandurantin-A and rutin. The synthetic drugs were majorly the widely used antivirals and some antimalarial moieties such as acyclovir, celgosivir, tenofovir, sofosbuvir, oseltamivir, emtricitabine and amodiaquine.[10],[12],[13],[14],[15],[16],[17]
Table 1: The list of compounds employed for docking

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Absorption, distribution, metabolism and elimination or excretion parameters evaluation

The compounds were evaluated for the parameters like total polar surface area, log P, molecular weight (MOLwt), hydrophilic and hydrophobic component to check their drug likeness property. These properties were evaluated using Qikprop module of Schrodinger. The compounds should comply the limits of varied parameters, to pass through the cellular membrane. Lipophilicity parameter logPcan aid prediction of passive absorption, distribution and clearance of compounds.[18],[19] Mol_MW denotes molecular weight (the limits range from 130.0 to 725.0). Total solvent accessible surface gives information of the structural and conformational attributes of the molecule, which may influence the ability of the compounds to interact with the environment in which it is present.[20],[21],[22] Total Solvent Accessible Surface Area known as SASA (square angstroms units) measured with a probe of 1.4 A° radius limit ranges 300.0–1000.0. FOSA represents hydrophobic component of the SASA (saturated carbon and attached hydrogen) (The limit ranges 0.0–750.0). FISA is the hydrophilic component of the SASA (H, O, N on heteroatoms) (the limit ranges 7.0–330.0). QP logP o/w indicates predicted octanol/water partition coefficient ranging from −2.0 to 6.5.[22]

Molecular docking

Preparation of protein and site mapping

The protein preparation wizard of Maestro in Schrodinger tool was used to prepare the crystal structure of the protein and was subjected to docking studies. Crystal docking process requires parameters such as bond orders and ionisation states to be properly assigned. Protein pre-processing was carried out to obtain these assigned parameters. The waters and heteroatoms present in the crystal structure were deleted. Energy minimisation was done to atoms movement and to relax strained bonds and angle. Different potential drug-binding sites were identified using protein site mapping application of Schrodinger.[23]

Preparation of ligand

The compounds were obtained through a literature search. A total of 15 were sketched using Schrodinger Ligand sketcher and prepared with Ligprep. The possible chemical states of drawn structures were prepared. The pre-processing was carried out in which the bond orders were assigned, along with the addition of hydrogens and deletion of water molecules. Further, the heterostates of the ligands if present were generated. H-bonding was optimised.[24]


Glide runs the docking in two steps:

  1. Receptor grid generation: Receptor grid represents the active site of the receptor for favourable interactions with the docked ligand molecules. It is formed using receptor grid generation application of protein preparation wizard
  2. Ligand docking: Glide is used for docking compounds into the protein molecules. The molecules were docked using extra precision. Glide energy of the docked compounds were computed. Compounds with lower Glide energy show better binding interaction with the amino acids present in the favourable protein sites. The more negative value of the glide energy represents tight binding compounds.[25]

  Results Top

The molecules analysed for ADME parameters showed that the parameters such as lipid solubility and solvent accessible area comply with the given range. The molecules such as amodiaquine and Pandurantin-A may show lipophilicity while the rest show hydrophilic properties. The molecules also comply the limits [Table 2] for molecular weights, SASA properties suggesting that these compounds may have the required drug like properties.
Table 2: Results of the ADME parameters evaluated using Qikprop application

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Site mapping

a total of four sites were identified [Figure 2] which can act as ligand-binding sites. In ligand docking, we identified some class of natural compounds that were assumed to be potential antiviral agents, based on docking studies and literature search.
Figure 2: The sites identified using site mapping module on the protein surface that may be conducive for binding of ligands. The dash outline represents the four favourable sites present on the dengue viral envelope protein.

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The compound rutin shows the highest dock score [Table 3] against the first favourable binding site of the envelope protein in comparison to other compounds from natural sources and synthetic molecules. In addition compounds such as quercetin and gallic acid pandurantin-A also show a comparable dock score to rutin. Among the synthetic antiviral class of compounds, acyclovir shows higher score compared to other synthetic antivirals and antiparasitic agents but lower than rutin. The compounds with lower energy show greater binding efficiency. The docking score and glide energy of rutin [Table 4] suggest that it may have greater interaction with most of the sites and on the first favourable site in a better manner. The molecular orientation image [Figure 3] shows that rutin occupies the site present on the protein with molecular interactions like van der Waals interaction, hydrogen bonding with different amino acids.
Table 3: Represents docking score and glide energy of different compounds at the first favourable site

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Table 4: Docking score and glide energy of rutin at all four sites

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Figure 3: The molecular fit of rutin in the favourable site of the protein. a and b show the interaction of rutin with the protein binding site 1 and 2. The yellow dotted lines denote the hydrogen bond interaction between the functional groups of the drug and amino acids of the protein. The green dotted lines represent all the favourable interactions of the functional groups of the drug and amino acids of the protein. c and d represent the two-dimensional images of a and b.

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At the active site [mentioned in [Table 5] one of the major interactions are observed with cysteine 3, arginine 2 and threonine 155. The amino acids tyrosine 132, asparagine 194 and tyrosine 137 at site two show interaction with most of the drugs while glycine 266, threonine 268 and leucine 207 are seen interacting with the drug molecules at the third site. The amino acids are present at their specified sites may prove crucial for the ligand interaction.
Table 5: Molecular drug interaction with amino acids at different sites

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  Discussion Top

The DENV surface comprises of two vital proteins, namely the membrane protein (M) and the envelope glycoprotein (E). Envelope proteins are glycosylated and arranged in homodimers on the viral surface. This surface glycoprotein is made up of three domains, namely the central Domain I, that is flanked on one side by Domain II. The Domain II contains the hydrophobic fusion loop. This loop lies in a pocket between the opposing E protein dimer units and is involved in fusion of the host cells and the virions. Domain III is located on the opposite side of Domain I, and it contains an immunoglobulin-like structure that is involved in host cell binding.

Dimers of the E protein are densely packed and arranged in a repetitive manner to form the virus particle. It is observed that it is the only protein exposed on mature virus particles. It is responsible in receptor binding and entry into susceptible cells.[26],[27] Till date, extensive researches are constantly been performed to develop drug candidate against this infection but these efforts have been mostly on symptomatic lines. Hence, there is a need to design new approaches to combat this viral infection.[28] Use of natural pharmaceuticals like medicinal plants may prove an efficient treatment for this problem. One of the popular computational techniques used in medical researches is molecular docking. It is used to find the binding probabilities of small molecules against their target proteins. This technique proves helpful in providing a clear molecular vision in identification of novel inhibitory compounds against fatal viral infections.[29],[30]

This study is an approach towards identification of the potential molecules that may prove effective against the DENV. We identified compounds from both naturally occurring source and synthetic, using in silico tools to elucidate and decipher their interaction of the DENV E protein. These findings may further aid in identification of more compounds belonging to the similar classes with an aim to pave way for effective treatment against dengue.

  Conclusion Top

The docking of different drug candidates was carried out. The compounds such as rutin, gallic acid, ellagic acid and celgosivir showed to have better binding based on their dock score and glide energy. Several interaction were observed between the ligand and the protein binding pocket like hydrogen binding, van der Waals interaction. The ligands showed interaction with cysteine 3, arginine 2, threonine 155, tyrosine 132, asparagine 194, tyrosine 137, glycine 266, threonine 268 and leucine 207 present in the active sites of the protein. Finally, it was observed that compounds from natural sources showed better binding than those of the synthetic antivirals against the dengue viral envelope protein.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3]

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


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