Exploring the Inhibitory Potential of Thiazolidinedione based drugs against HN, F, M and N Proteins of NDV through Computational Analysis

Abstract

The Newcastle Disease Virus (NDV), primary pathogen responsible for Newcastle Disease (ND) infection in poultry, is classified as an avian paramyxovirus type I and possesses an outer protective layer. The viral genome consists of a single-stranded RNA molecule with a negative-sense orientation, measuring around 15.2 kilobases in length. This RNA molecule encodes a total of six distinct proteins. Four structural proteins including HN, F, M and NP are regarded as promising therapeutic targets owing to their crucial role in viral replication cycle. There are currently no NDV specific antiviral agents/therapeutics available in the poultry industry and due to the ineffectiveness of commercial live attenuated vaccine, outbreaks of this disease are frequently observed within the chicken business, resulting in substantial economic repercussions. The Thiazolidinedione based drugs known for their anti diabetic, anti-microbial, anti-tumor, anti-viral, anti-inflammatory, and anti-cancer properties have been repurposed as anti-NDV drugs through computational methods. Nevertheless, there has not been a single study about these Thiazolidinedione based drugs reported against NDV. Therefore, the present study has been conducted to explore the inhibitory potential of 10 Thiazolidinedione based drugs against four essential structural proteins of Newcastle Disease Virus i.e., HN, F, M and NP. Significant and encouraging outcomes have been shown for the following compounds: HN/Troglitazone (-9.2 kcal/mol), HN/Englitazone (-9.1 kcal/mol), NP/Troglitazone (-8.6 kcal/mol), and F/Balaglitazone (-7.8 kcal/mol). In a similar vein, the compounds M/Rosiglitazone and M/Ciglitazone have demonstrated potential positive results, with respective binding energies of -8.4 kcal/mol and -8.1 kcal/mol. The structural flexibility of the HN/Troglitazone, HN/Englitazone, NP/Troglitazone, and F/Balaglitazone docking complexes was confirmed by MD simulations, as evidenced by the root mean square fluctuation (RMSF) values below 5Å. The study's findings indicated that Troglitazone, Englitazone, Balaglitazone, Rosiglitazone, and Ciglitazone have the most xvi effective antiviral therapeutic potential against Newcastle Disease infections. Additional in vitro and in vivo evaluation to better understand the molecular complexity of therapeutic and antiviral capabilities will increase researchers' chances of finding innovative therapeutics throughout the drug development process.