Dynamics of natural product Lupenone as a potential fusion inhibitor against the spike complex of novel Semliki Forest Virus.

Nobendu Mukerjee,Punya Sachdeva,Abhijit Dey,Debabrat Baishya,Anubhab Das,Athanasios Alexiou,Swastika Maitra,Faizan Ahmad,Muhanna K Al-Muhanna,Arabinda Ghosh,Prattusha Khan,Vijay Kumar

doi:10.1371/journal.pone.0263853

Abstract

The Semliki Forest Virus (SFV) is an RNA virus with a positive-strand that belongs to the Togaviridae family’s Alphavirus genus. An epidemic was observed among French troops stationed in the Central African Republic, most likely caused by the SFV virus. The two transmembrane proteins El and E2 and the peripheral protein E3 make up the viral spike protein. The virus binds to the host cell and is internalized via endocytosis; endosome acidification causes the E1/E2 heterodimer to dissociate and the E1 subunits to trimerize. Lupenone was evaluated against the E1 spike protein of SFV in this study based on state-of-the-art cheminformatics approaches, including molecular docking, molecular dynamics simulation, and binding free energy calculation. The molecular docking study envisaged major interactions of Lupenone with binding cavity residues involved non-bonded van der Waal’s and Pi-alkyl interactions. Molecular dynamic simulation of a time scale 200 ns corroborated interaction pattern with molecular docking studies between Lupenone and E1 spike protein. Nevertheless, Lupenone intearcation with the E1 spike protein conforming into a stable complex substantiated by free energy landscape (FEL), PCA analysis. Free energy decomposition of the binding cavity resdiues of E1 spike protein also ensured the efficient non-bonded van der Waal’s interaction contributing most energy to interact with the Lupenone. Therefore, Lupenone interacted strongly at the active site conforming into higher structural stability throughout the dynamic evolution of the complex. Thus, this study perhaps comprehend the efficiency of Lupenone as lead molecule against SFV E1 spike protein for future therapeutic purpose.

Highlights

Semliki Forest Virus (SFV) is a positive-stranded RNA virus that belongs to the Alphavirus genus of the Togaviridae family
Oligodendrocytes, neurons, and plexus cells were the only cells in the central nervous system infected by all of the different strains. These cells were the only cells that were infected by any of the strains. In both animals and humans, it has been linked to the transfer of disease; according to scientific studies, SFV [3] was identified as the likely source of an outbreak among French troops stationed in the Central African Republic after a case of the virus was confirmed among the soldiers
Docking experiments of the protein-ligand complex were carried out using Genetic Algorithm (GA) parameters were set with 100, population size was made 200 with maximum number of evals was set to low at 2500000 and maximum generations of 27000

Summary

Introduction

Semliki Forest Virus (SFV) is a positive-stranded RNA virus that belongs to the Alphavirus genus of the Togaviridae family. The virus was first isolated in Semliki Forest, Uganda, from mosquitoes (Aedes aegypti) [1] This is surprising and contradictory as this virus, which had undergone significant research, was previously regarded as one of the arboviruses that are non-hazardous to people [2]. It is probable that SFV, like other members of the Alphaviruses (such as the Chikungunya virus, the O’nyong’nyong viral strain (O’nyong’nyong virus), the Sindbis virus (Sindbis virus), the Ross River virus (Ross River virus), and others, will evolve into a health danger to humans). This finding is supported by evidence from mouse models to human infections and the few known human infections

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