A rational structure-based drug design strategy for the discovery of novel antiviral agents against the Yellow Fever Virus helicase

Abstract

Yellow Fever is a viral hemorrhagic disease that is transmitted mainly through arthropods with high mortality rates. Yellow Fever Virus (YFV) is an enveloped positive sense single-stranded RNA virus, member of the Flaviviridae family and the Flavivirus genus, and is endemic in countries of Africa and South America. However, recent cases of infection in North America, Asia and Europe are highlighting the potential risk of an outbreak with no effective treatment available and the urgent need to develop potent antiviral agents against the YFV. In this direction a range of specific modulators were designed and in silico evaluated in an effort to hinder the enzymatic activity of the YFV helicase as a prominent pharmacological target. Following a structure-based rational drug design pipeline, a phylogenetic analysis of Flaviviridae viruses and an in-depth evolutionary study on the Yellow Fever Virus helicase has provided invaluable insights into structural conservation and structural elements and features that are vital for the viral helicase function. Using comparative modelling and molecular dynamics simulations the YFV helicase-ssRNA complex was established, and the specific molecular interactions and physicochemical properties of the complex could be analyzed and used towards the designing and elucidation of a specific YFV 3D pharmacophore model. A high throughput virtual screening simulation was conducted to assess a set of in-house maintained low molecular weight compounds as bioactive inhibitors of the YFV helicase enzyme. The in-silico study described herein, could pave the way towards the designing and more efficient screening of potential novel modulator compounds against the YFV as well as attest and designate the NS3 helicase as an antiviral pharmacological target of uttermost value and potential.