|Year : 2018 | Volume
| Issue : 2 | Page : 60-63
In silico drug discovery of novel small lead compounds targeting nipah virus attachment glycoprotein
Ashish P Shah, Bhumika M Parmar, Mubasarin A Ghodawala, Avinashkumar Seth
Department of Pharmacy, Sumandeep Vidyapeeth, Vadodara, Gujarat, India
|Date of Web Publication||26-Feb-2019|
Ashish P Shah
Department of Pharmacy, Sumandeep Vidyapeeth, Vadodara, Gujarat
Source of Support: None, Conflict of Interest: None
Introduction: Nipah virus (NiV) and Hendra virus are the type species of the highly pathogenic paramyxovirus genus Henipavirus, which can cause severe respiratory disease and fatal encephalitis infections in humans. NiV contains two envelope glycoproteins, the receptor-binding G glycoprotein (NiV-G) that facilitates attachment to host cells and the fusion (F) glycoprotein that mediates membrane merger. The attachment glycoprotein (NiV-G) on the surface of the virus is an important virulent factor and a promising antiviral target. In vitro, favipiravir inhibited Nipah and Hendra virus replication and transcriptionat micro molar concentrations. Experimental: In this study, we had designed ten bioisosteres of favipiravir containing pyrazine or quinoxaline moeity to identify novel inhibitors of Nipah virus using different in silico methods. The molecular docking studies were performed using iGEMDOCK2.1. Drug likeness of the compounds was predicted using SwissADME online tool. In silico toxicity studies were performed using ProTox-II. The comparison of in silico results were done with standard drug favipiravir. Results: In the docking studies, eight compounds showed significant inhibitory activity with low docking score as compare to standard drug. All the designed molecules had drug likeness properties and predicted to be nontoxic. Conclusion: These findings indicate that the novel bioisosteres of favipiravir have promising potential to target NiV-G/ephrin interactions to disrupt viral entry and provide the foundation for structure-based antiviral drug design.
Keywords: Favipiravir, in silico drug design, Nipah virus attachment glycoprotein, small lead molecules
|How to cite this article:|
Shah AP, Parmar BM, Ghodawala MA, Seth A. In silico drug discovery of novel small lead compounds targeting nipah virus attachment glycoprotein. J Integr Health Sci 2018;6:60-3
|How to cite this URL:|
Shah AP, Parmar BM, Ghodawala MA, Seth A. In silico drug discovery of novel small lead compounds targeting nipah virus attachment glycoprotein. J Integr Health Sci [serial online] 2018 [cited 2019 May 22];6:60-3. Available from: http://www.jihs.in/text.asp?2018/6/2/60/252874
| Introduction|| |
Nipah virus (NiV) is zoonotic virus of the family paramyxovirida e, genus Hanipavirus. In 1999, NiV was first identified in Malaysia and Singapore. There were nearly 300 human cases with over 100 deaths were reported due to encephalitis and respiratory illness caused by NiV infection. In May 2018, the first outbreak of NiV infection was reported in Kerala, India. There is no vaccine or specific treatment reported to cure this infection. Several fruit bats have been identified as the vector of NiV virus. Novel anti-viral strategies are useful to find out molecular mechanisms of virus development process. The structure of NiV contains the attachment glycoprotein (G) protein composed of 602 amino acid residues. They are type II membrane glycoprotein having functions as a receptor binding protein. This G protein provides attachment to host cell receptors and plays a significant role in the replicationprocess of the viral nucleic acid in the host cell.,, Favipiravir is a purine analogue antiviral drug which has efficacy against a broad spectrum of RNA virus.In vitro favipiravir inhibited NiV replication and transcription at micromolar concentration.
Nowadays, computer-aided drug design is one of the important techniques of rational drug design. This in silico study involves different computational techniques which help to reduce time and cost of drug discovery process. High-throughput robotic screening method is time consuming, as more number of compounds must be trialled. Structure-based drug design is useful to find out new lead compound which is active against the target. This process required lesser number of compounds that may take into the trial. In this study, we had designed ten bioisosteres of fevipiravir containing pyrazine and/or quinoxaline moiety to identify novel inhibitors of NiV using different in silico methods. The molecular docking studies were performed using iGEMDOCK2.1. Drug likeness of the compounds was predicted using SwissADME online tool. In silico toxicity studies were performed using ProTox-II. The comparison of in silico results were done with standard drug fevipiravir.
| Experimental|| |
Preparation of ligands
The structure of designed ligands [Figure 1] was drawn using ChemBioDraw Ultra 12.0 in 2Dformat. Then, these two-dimensional structures were exported to ChemBio3D Ultra 12.0 for the energy minimization and geometry correction. Then, outputs of the structures were saved in mol file which was directly used for docking and absorption, distribution, metabolism, excretion and toxicity (ADMET) studies.
Preparation of protein
Crystal three-dimensional (3D) structure of protein (PDB id: 3D11) was downloaded from protein data bank in the PDB format. Structure of proteins was evaluated based on of Ramachandran plot using RAMPAGE [Figure 2]. It was described by Ramachandran plot that 386 (90.8%) residues of the predicted model of protein were in favored region while 36 (8.5%) were in allowed region and 3 (0.7%) were in outlier region. Protein was energy minimized, water molecules were removed, and hydrogen and charges were added. Finally, 3D structures of protein saved in PDB format and directly used for preliminary screening and analysis for docking using iGEMDOCK.
Docking, screening and postanalysis of the design molecules were done using iGEMDOCK program with the protein targets 3D11. The binding sites of the targets were prepared and the energy minimized compound was imported. From the docking, wizard ligands were selected and the scoring function used was iGEMDOCK score. The binding site of the target was 8Š. The empirical scoring function of iGEMDOCK was estimated as: Fitness = vdW + Hbond + Elec.
In silico absorption, distribution, metabolism, excretion and toxicity studies
Compounds ADMET profile plays crucial role in discovery of new drug. A Compound has to pass multiple filters to be considered as drug like molecule. Pharmacokintetic properties of designed compounds were predicted using SwissADME online software tool. In silico toxicity studies useful to avoid or reduce animal experiments. The in silico toxicity studies were performed using ProTox-II online tool. The properties such as organ toxicity, carcinogenicity, mutagenicity, cytotoxicity, and toxicity class were predicated.
| Results And Discussion|| |
Molecular docking studies
The molecular interactions of all design molecules with various proteins and prefer orientation were identified by performing molecular docking studies. The binding affinity (docking score) were compared with standard drug fevipiravir [Table 1]. Out of the ten design molecules, eight showed significant inhibition with lower docking score as compared to standard drug. Visualization of 3D interactions and orientation of molecules were done using PyMol visualization tool. Molecular interactions of Fevipiravir (A), N8 (C) and N10 (E) with various amino acids residues of protein mentioned in [Figure 3].
|Figure 3: Interactions of Fevipiravir (a), N8 (c) and N10 (e) with various amino acids residues of NiV-G and orientation of Fevipiravir (b), N8 (d) and N10 (f) in binding pocket of NiV-G|
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In silico ADMET analysis
The ADME properties of design molecules mentioned in [Table 2]. Drug likeness of the compounds was evaluated on the basis of Lipinski rule of five. All designed compounds shows no violations as per Lipinski rule. Total polar surface area is important property to find out polarity of molecule, which is also important for intestinal absorption, bioavailability, blood brain barrier penetration etc. Compounds with polar surface area greater than 140Š have poor cell membrane permeability. All the design molecules have polar surface are less than 140Š. Results of in silico toxicity studies shows that all the design molecules were belong to toxicity class 4 [Table 3].
| Conclusion|| |
NiV contains two envelope of glycoprotein, the receptor-binding G glycoprotein (NiV-G) that facilitates attachment to host cells and the fusion (F) glycoprotein that mediates membrane merger. The attachment glycoprotein (NiV-G) on the surface of the virus is an important virulent factor and a promising antiviral target. All the design molecules showed significant inhibitory activity, drug likeness property and predicted nontoxic. This finding indicates that the novel bioisosteres of favipiravir have promising potential to target NiV-G/epherin interactions to disrupt viral entry and provide the foundation for structure-based antiviral drug design.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]