Unveiling of Pyrimidindinones as Potential Anti-Norovirus Agents-A Pharmacoinformatic-Based Approach.

Oluwakemi Ebenezer,Nkululeko Damoyi,Michael Shapi,Maryam A Jordaan

doi:10.3390/molecules27020380

Oluwakemi Ebenezer, Nkululeko Damoyi + Show 2 more

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https://doi.org/10.3390/molecules27020380

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Abstract

The RNA-dependent RNA polymerase (RdRp) receptor is an attractive target for treating human norovirus (HNV). A computer-aided approach like e-pharmacophore, molecular docking, and single point energy calculations were performed on the compounds retrieved from the Development Therapeutics Program (DTP) AIDS Antiviral Screen Database to identify the antiviral agent that could target the HNV RdRp receptor. Induced-fit docking (IFD) results showed that compounds ZINC1617939, ZINC1642549, ZINC6425208, ZINC5887658 and ZINC32068149 bind with the residues in the active site-B of HNV RdRp receptor via hydrogen bonds, salt bridge, and electrostatic interactions. During the molecular dynamic simulations, compounds ZINC6425208, ZINC5887658 and ZINC32068149 displayed an unbalanced backbone conformation with HNV RdRp protein, while ZINC1617939 and ZINC1642549 maintained stability with the protein backbone when interacting with the residues. Hence, the two new concluding compounds discovered by the computational approach can be used as a chemotype to design promising antiviral agents aimed at HNV RdRp.

Highlights

At times, norovirus can be referred to as a winter vomiting bug or food poisoning and is the most common cause of gastroenteritis contagion in mammalian hosts
CMX521, a derivative of sangivamycin, is a nucleoside analog of ribofuranose [2]. This molecule is another nucleoside analog of ribofuranose that potently suppresses murine norovirus (MNV) in mice and was the first nucleoside analog to be moved to clinical trials for the prevention and treatment of human norovirus [2,18]
The crystal structure of human norovirus (HNV) RNA-dependent RNA polymerase (RdRp) consists of a site-A and site-B

Summary

Introduction

Norovirus can be referred to as a winter vomiting bug or food poisoning and is the most common cause of gastroenteritis contagion in mammalian hosts. ORF1 encodes the polyproteins that are cleaved into six non-structural proteins (p48 (NS1/2), NTPase (NS3), p22 (NS4), VPg (NS5), along with the virus-encoded 3C-like cysteine protease (3CLpro) and a viral RNAdependent RNA polymerase (RdRp) [2]. CMX521, a derivative of sangivamycin, is a nucleoside analog of ribofuranose [2] This molecule is another nucleoside analog of ribofuranose that potently suppresses murine norovirus (MNV) in mice and was the first nucleoside analog to be moved to clinical trials (phase 1) for the prevention and treatment of human norovirus [2,18]

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