Virtual screening of phytochemicals from Indian medicinal plants against the endonuclease domain of SFTS virus L polymerase.

R P Vivek-Ananth,Ashutosh Srivastava,Areejit Samal,Ajaya Kumar Sahoo

doi:10.1039/d1ra06702h

Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV) causes a highly infectious disease with reported mortality in the range 2.8% to 47%. The replication and transcription of the SFTSV genome is performed by L polymerase, which has both an RNA dependent RNA polymerase domain and an N-terminal endonuclease (endoN) domain. Due to its crucial role in the cap-snatching mechanism required for initiation of viral RNA transcription, the endoN domain is an ideal antiviral drug target. In this virtual screening study for the identification of potential inhibitors of the endoN domain of SFTSV L polymerase, we have used molecular docking and molecular dynamics (MD) simulation to explore the natural product space of 14 011 phytochemicals from Indian medicinal plants. After generating a heterogeneous ensemble of endoN domain structures reflecting conformational diversity of the corresponding active site using MD simulations, ensemble docking of the phytochemicals was performed against the endoN domain structures. Apart from the ligand binding energy from docking, our virtual screening workflow imposes additional filters such as drug-likeness, non-covalent interactions with key active site residues, toxicity and chemical similarity with other hits, to identify top 5 potential phytochemical inhibitors of endoN domain of SFTSV L polymerase. Further, the stability of the protein–ligand docked complexes for the top 5 potential inhibitors was analyzed using MD simulations. The potential phytochemical inhibitors, predicted in this study using contemporary computational methods, are expected to serve as lead molecules in future experimental studies towards development of antiviral drugs against SFTSV.

Highlights

Severe fever with thrombocytopenia syndrome virus (SFTSV), known as Huaiyangshan banyangvirus, is a segmented negative-sense RNA virus[1,2] that causes severe fever with thrombocytopenia syndrome (SFTS)
The root mean square deviation (RMSD) of the Ca atoms of the endoN residues and Mn2+ ions remain stable during the molecular dynamics (MD) simulations with RMSD values largely within 3 A (Fig. 2a)
This indicates that the endoN domain structure remains compact during the MD simulations (Fig. 2b)

Summary

Introduction

SFTSV, known as Huaiyangshan banyangvirus, is a segmented negative-sense RNA virus (sNSV)[1,2] that causes severe fever with thrombocytopenia syndrome (SFTS). SFTS is suspected to be a tick-borne disease,[3] human-to-human transmissions through direct contact with contaminated blood or tissue samples of infected person have been reported.[4,5,6] SFTS is characterized by clinical symptoms such as high fever, thrombocytopenia, leukopenia, gastrointestinal disorder and multiple organ dysfunction.[2,7] The rst cases of SFTS were reported from China in 2009,8 and therea er, cases have been reported from Japan, Korea, Vietnam and Taiwan.[3] The reported mortality from SFTSV infection varies considerably across countries. While Japan and South Korea have reported a high

Methods

Results

Conclusion