Exploration and Validation of Lead Molecules against Yellow Fever through High Throughput Virtual Screening and Molecular Dynamics Simulation

Abstract

Background: Yellow fever (YF) is a mosquito-borne flaviviral hemorrhagic fever (VHF) that causes severe hepatitis, renal failure, bleeding, and quick terminal events such as shock and multi-organ failure. There are currently no particular anti-viral medications for the management of the YF virus (YFV). Despite the availability of a commercial YFV vaccination, there are roughly 30,000 fatalities globally each year, with instances rising over the previous 20 years. After being translocated into the endoplasmic reticulum lumen, glycosylated NS1 resides as a membrane-associated dimer, where it is required for viral genome replication. The secreted hexamer NS1 has a role in immune evasion and pathogenesis and has been discovered as a possible diagnostic marker for the early identification of viral infections. Objective: The main aim of this study is to analyze the small molecule as a potent drug candidate against the target NS1 protein. Methods: In this study, Computational approaches, including high throughput virtual screening, molecular docking, and dynamics simulation, were carried out against the target NS1 protein using three different chemical libraries Enamine, Asinex, and NCI. The selected lead compounds were validated through HOMO-LUMO analysis, ADME prediction, and Toxicity parameters to analyze the biological and pharmacological properties of the lead small molecules. Results: From the result, it was concluded that the leads possessed the highest docking scores, interacting with the binding residues, and were stable in the simulation period. Conclusion: Overall findings revealed that the lead three small molecules could act as the potential drug candidate for the target NS1 protein to inhibit the diseasing efficacy of Yellow fever.