Exploring NS5 Protein as a Potential Target for Antiviral Development in Yellow Fever: Insights from Molecular Docking & Molecular Dynamics Simulations

Abstract

Yellow fever is an infectious disease caused by the Flaviviridae family of viruses. It is spread by the bite of an infected mosquito, Aedes aegypti. It is found in 47 nations throughout Africa and Central and South America, with an estimated 400-500 million individuals living in high-risk regions unvaccinated. Symptoms range from mild to severe, with moderate symptoms such as a fever, headache, aches, pains, nausea, vomiting, and exhaustion. In more severe cases, the illness may develop to a more hazardous stage, known as the toxic phase, which is characterized by high fever, jaundice, organ failure, and hemorrhage. Vaccination and treatment are available, but there is no specific antiviral treatment for yellow fever. The genome of YFV consists of 11 kilobases of RNA and the UTR at 5'-3' end encodes for 10 proteins. The NS5 protein is of interest to researchers as it acts as a major enzyme in the process by which flaviviruses replicate. It is made up of two essential domains, the N-terminal methyltransferase (MTase) domain and the C-terminal RNA-dependent RNA polymerase (RdRp) domain respectively. These domains are necessary for the virus to replicate successfully in its host. Inhibiting the action of NS5 could affect the replication of flaviviruses and offer a way for the development of antiviral medicines. Gamma-glutamyl-S-allyl-L-cysteine has the highest docking score of -12.5 Kcal/mol with the target NS5 protein of YFV. Ligplot shows 12 H-bonds being formed, and GROMACS molecular dynamics simulation shows an average of 3.09 H-bonds present over 500 ps. The polymerase also shows similarity to Zika and Dengue virus polymerase, suggesting it could be a potent inhibitor of their replication.