COMPUTATIONAL PREDICTION OF PYRETHROIDS AS PROMISING AGENTS AGAINST RESPIRATORY SYNCYTIAL VIRUS : A COMPARATIVE STUDY

Pyrethrin; derived from natural source (Chrysanthemum cinerariifolium) confirmed as a fundamental nucleus for the development of pyrethroids which ultimately resulted in the outstanding insecticidal activity by targeting the nervous systems of insects. To date, the binding and entry mechanism by which RSV infects respiratory epithelial cells is not still well understood and need to be explored. Notably, pyrethrins have exhibited considerable antiviral potential & thus an effort was made computationally to evaluate the pyrethroids as hopeful inhibitors of Respiratory Syncytial Virus (RSV). Type 1 & type 2 Pyrethroids were subjected to docking simulations by using Maestro 9.2 version (Schrodinger LLC). Cyfluthrin showed better binding interactions against RSV (Glide score: -4.54). Remarkably, it showed two hydrogen bonding interactions with Lys46 (1.82 Å) & Hie151 (2.19 Å) of RSV protein receptor. The decrease in glide score is evidence for greater bond stability with protein. Based on the current findings, these studies in future may act as effective predecessor tool to further validate pyrethroids with wet lab experiments as capable antiviral agents for RSV.


INTRODUCTION
For the infant and young children respiratory syncytial virus (RSV) serves as an important precursor for the development of bronchiolitis.According to WHO, RSV showed accountability alone for more than 60% of acute respiratory infections in children worldwide.More than 80% of infant younger than 1 year suffered from lower tract infection during the peak viral season. 1 Previous studies have indicated that at the age of 2 to 3 month (lowest IgG concentration), the infections happened mostly with no time.The host responses to RSV infection depend on magnitude and intensity of infection. 2RSV belongs from the family paramyxoviridne which is a single stranded RNA virus.The genome compromises of ten genes that encodes for eleven different proteins.The major antigen F protein and the G glycoprotein these are two surface proteins these are responsible for the virulence of the RSV.Till date, there is no specific drug of choice for the treatment of RSV infection and the drugs which are already available in the market posses certain drawbacks such as binfant suffered from congenital heart disease & chronic lung diseases, respectively. 3Pyrethin is a chief phytoconstituent of Chrysanthemum cineraraefolum which serves as an important predecessor for the development of pyrethroids.Pyrethroids are widely used in home and agriculture as insecticides to control the pest.Human are exposed to pyrethroid by various mode like air, water, vegetables, etc at low concentration and it's safe to humans.Deltamethrin and fenvalerate are chemically type 2 pyrethroids which show α-cyano phenoxy benzyl moiety while the type 1 pyrethroids such as permethrin lack this moiety. Synthetic pyrethroids reported as hemopiosons which act on the axons and in the central nervous system by interfering with sodium channel in mammals or in insects. 6 Hata et al., 2011   demonstrated that at a concentration of 4-12 μM, pyrethrin showed antiplasmodial activity while between 7 to 31 μM showed antitrypanosomal action.On the other hand, the efficacy of pyrethrin analogues formulations were also examined against vector diseases. 7The literature report has indicated the pyrethrins role as antiviral source & thus an attempt was made to evaluate the pyrethroids as expectant inhibitors of Respiratory Syncytial Virus (RSV). 8To date, the binding and way in mechanism by which RSV infects respiratory epithelial cells is still

Protein preparation
The 3-dimensional protein structure (PDB: 4UCC) was retrieved from RCSB protein site in PDB format 9 & exported into Maestro software.Protein pre-processes was done by addition of polar hydrogen and removal of metal ions, cofactor and water molecule outside 5Å.The ionization (PH: 6.7-7.3),optimization of hydrogen bond and restorative energy minimization have executed to receptors molecule, an essential step to the correct geometry of receptors.

Ligand library
With the help of Chem draw ultra 10.0 (Cambridge soft) the structure were drawn and tested compounds were saved in three dimensional structure (.mol format) and then plot into maestro project table.Least square OPLS_2005 force field is used to complete the ligands preparations plus energy minimization.Furthermore, generations of conformers plus energy minima were performed to enhance the stability of ligands with the receptor.

Grid generation & docking assessment
XP visualize was used for the docking pose analysis.The binding pocket having the electrostatic and vander wall's potential was assigned through grid box.The in-silico docking results should analysed not only on the basis of glide score but also different type of interactions of tested molecules with the receptor. 10

Resmethrin
It was also placed among top ranked hits (second rank) with glide score as indicated in Table 1.

Figure 2 :
Figure 2: Binding interactions of Cyfluthrin with RSV protein receptor.

Figure 3 :
Figure 3: Binding interactions of Resmethrin with RSV protein receptor.

Figure 4 :
Figure 4: Binding interactions of Permethrin with RSV protein receptor.