Computational screening of medicinal plant phytochemicals to discover potent pan-serotype inhibitors against dengue virus

Muhammad Tahir Ul Qamar,Iqra Muneer,Usman Ali Ashfaq,Faheem Ahmed Khan,Arooma Maryam,Feng Xing,Rana Rehan Khalid,Farooq Anwar,Abdul Rauf Siddiqi,Sadaf Abdul Rauf,Mohammed H Geesi

doi:10.1038/s41598-018-38450-1

Abstract

Emergence of Dengue as one of the deadliest viral diseases prompts the need for development of effective therapeutic agents. Dengue virus (DV) exists in four different serotypes and infection caused by one serotype predisposes its host to another DV serotype heterotypic re-infection. We undertook virtual ligand screening (VLS) to filter compounds against DV that may inhibit inclusively all of its serotypes. Conserved non-structural DV protein targets such as NS1, NS3/NS2B and NS5, which play crucial role in viral replication, infection cycle and host interaction, were selected for screening of vital antiviral drug leads. A dataset of plant based natural antiviral derivatives was developed. Molecular docking was performed to estimate the spatial affinity of target compounds for the active sites of DV’s NS1, NS3/NS2B and NS5 proteins. The drug likeliness of the screened compounds was followed by ADMET analysis whereas the binding behaviors were further elucidated through molecular dynamics (MD) simulation experiments. VLS screened three potential compounds including Canthin-6-one 9-O-beta-glucopyranoside, Kushenol W and Kushenol K which exhibited optimal binding with all the three conserved DV proteins. This study brings forth novel scaffolds against DV serotypes to serve as lead molecules for further optimization and drug development against all DV serotypes with equal effect against multiple disease causing DV proteins. We therefore anticipate that the insights given in the current study could be regarded valuable towards exploration and development of a broad-spectrum natural anti-dengue therapy.

Highlights

Emergence of Dengue as one of the deadliest viral diseases prompts the need for development of effective therapeutic agents
Circos plot highlights broad hubs on three inner rims which clearly demonstrate high sequence conservation within confined regions of genomes that correspond to NS1, NS3 and NS5 protease of the four Dengue virus (DV) serotypes
It is noteworthy that 5′UTR region of all DV serotype genomes (DV 1–4) has low‚ while 3′UTR region has the highest level of GC %age

Summary

Introduction

Emergence of Dengue as one of the deadliest viral diseases prompts the need for development of effective therapeutic agents. Conserved non-structural DV protein targets such as NS1, NS3/NS2B and NS5, which play crucial role in viral replication, infection cycle and host interaction, were selected for screening of vital antiviral drug leads. This study brings forth novel scaffolds against DV serotypes to serve as lead molecules for further optimization and drug development against all DV serotypes with equal effect against multiple disease causing DV proteins. Dengue specific complexities linked to immune enhancement make it an extremely challenging task to design effective and broad spectrum anti-dengue therapeutic solutions[5]. These serotypes show antigenic variations in their envelope protein. NS1, NS3 and NS5 are crucial for the formation of the viral particle during infection cycle[6]

Objectives

Methods

Results

Conclusion