Targeting Dengue Virus NS-3 Helicase by Ligand based Pharmacophore Modeling and Structure based Virtual Screening.

Sobia A Halim,Javid Hussain,Ahmed Al-Harrasi,Shanza Khan,Ajmal Khan,Fazal Mabood,Abdul Wadood

doi:10.3389/fchem.2017.00088

Abstract

Dengue fever is an emerging public health concern, with several million viral infections occur annually, for which no effective therapy currently exist. Non-structural protein 3 (NS-3) Helicase encoded by the dengue virus (DENV) is considered as a potential drug target to design new and effective drugs against dengue. Helicase is involved in unwinding of dengue RNA. This study was conducted to design new NS-3 Helicase inhibitor by in silico ligand- and structure based approaches. Initially ligand-based pharmacophore model was generated that was used to screen a set of 1201474 compounds collected from ZINC Database. The compounds matched with the pharmacophore model were docked into the active site of NS-3 helicase. Based on docking scores and binding interactions, 25 compounds are suggested to be potential inhibitors of NS3 Helicase. The pharmacokinetic properties of these hits were predicted. The selected hits revealed acceptable ADMET properties. This study identified potential inhibitors of NS-3 Helicase in silico, and can be helpful in the treatment of Dengue.

Highlights

Dengue is one of the most common infections in tropical and subtropical countries, and one of the major diseases in Pakistan since 2005
Dengue is caused by dengue virus (DENV) which belongs to the Flavivirus genus of the Flaviviridae family (Lindenbach and Rice, 2003)
ZINC provides chemical molecules repositories that contain millions of diverse compounds. >1.2 million compounds were retrieved from the “Drug ” category of ZINC database

Summary

Introduction

Dengue is one of the most common infections in tropical and subtropical countries, and one of the major diseases in Pakistan since 2005. Over past few years around 48,910 cases appeared with 566 death cases. The first deadly outbreak was reported in Lahore in 2011, where 21,685 cases with 350 deaths were recorded (Lindenbach and Rice, 2003; Mukhtar et al, 2011; Ali et al, 2013; Khan et al, 2013, 2014, 2015, 2016; Rasheed et al, 2013; Raza et al, 2014), while about 50–100 million cases appeared worldwide. The infected dengue cases show several clinical symptoms including high fever, headache, muscular pain, and nausea/vomiting which can lead to serious conditions such as dengue shock syndrome (DSS) or dengue hemorrhagic fever (DHF). DSS/DHF can eventually cause death within 24 h. Till date no effective drugs are available to cure the disease completely (Kuhn et al, 2002; van Gorp et al, 2002; Seneviratne et al, 2006; Bhatt et al, 2013)

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