Application of Molecular Dynamics Simulations to the Design of Nucleotide Inhibitors Binding to Norovirus Polymerase.

Abstract

The RNA-dependent RNA polymerase (RdRp) of norovirus is an attractive target of antiviral agents aimed at providing protection against norovirus-associated gastroenteritis. Here, we perform molecular dynamics simulations of the crystal structure of norovirus RdRp in complex with several known binders, as well as free-energy simulations by free-energy perturbation (FEP) to determine binding free energies of these molecules relative to the natural nucleotide substrates. We determine experimental EC50 values and nucleotide incorporation efficiencies for several of these compounds. Moreover, we investigate the mechanism of inhibition of some of these ligands. Using FEP, we screened a virtual nucleotide library with 121 elements for binding to the polymerase and successfully identified two novel chain terminators.

• Authors: Holly Freedman, Juthika Kundu, Egor Petrovitch Tchesnokov, John Lok Man Law, James A Nieman, Raymond F Schinazi, D Lorne Tyrrell, Matthias Gotte, Michael Houghton
• Journal: Journal of chemical information and modeling (J Chem Inf Model) Vol. 60 Issue 12 Pg. 6566-6578 (12 28 2020) ISSN: 1549-960X [Electronic] United States
• PMID: 33259199 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Nucleotides
• RNA-Dependent RNA Polymerase

Topics

• Antiviral Agents (pharmacology)
• Molecular Dynamics Simulation
• Norovirus
• Nucleotides
• RNA-Dependent RNA Polymerase