Computer-aided Design of Wide-spectrum Coronavirus Helicase NSP13 Cage Inhibitors: A Molecular Modelling Approach.

Abstract

The coronavirus helicase NSP13 plays a critical role in its life cycle. The found NSP13 inhibitors have been tested only in vitro but they definitely have the potential to become antiviral drugs. Thus, the search for NSP13 inhibitors is of great importance. The goal of the present work was to develop a general approach to the design of ligands of coronaviral NSP13 helicase and to propose on its basis potential inhibitors. The structure of the NSP13 protein was refined by molecular dynamics and the cavity, responsible for RNA binding, was chosen as the inhibitor binding site. The potential inhibitor structures were identified by molecular docking and their binding was verified by molecular dynamics simulation. A number of potential NSP13 inhibitors were identified and the binding modes and probable mechanism of action of potential inhibitors was clarified. Using the molecular dynamics and molecular docking techniques, we have refined the structure of the coronavirus NSP13 helicase, a number of potential inhibitors, containing cage fragment were proposed and their probable mechanism of action was clarified. The proposed approach is also suitable for the design of ligands interacting with other viral helicases.