Abstract
Although vaccines that provide protection against severe illness from coronavirus disease (COVID-19) have been made available, emerging variant strains of severe acute respiratory syndrome 2 coronavirus 2 (SARS-CoV-2) are of concern. A different research direction involves investigation of antiviral therapeutics. In addition to structural proteins, the SARS-CoV-2 non-structural proteins are of interest and this includes the helicase (nsp13). In this study, an initial screen of 300 ligands was performed to identify potential inhibitors of the SARS-CoV-2 nsp13 examining the nucleoside triphosphatase site (NTPase activity) as the target region. The antiviral activity of polyphenols has been previously reported in the literature and as a result, the phenolic compounds and fatty acids from the OliveNet™ library were utilised. Synthetic compounds with antimicrobial and anti-inflammatory properties were also selected. The structures of the SARS-CoV and MERS-CoV helicases, as well as the human RECQ-like DNA helicase, DHX9 helicase, PcrA helicase, hepatitis C NS3 helicase, and mouse Dna2 nuclease-helicase were used for comparison. As expected, sequence and structural homology between the various species was evident. A number of broad-spectrum and well-known inhibitors interacted with the NTPase active site highlighting the need to potentially identify more specific inhibitors for SARS-CoV-2. Acetylcysteine, clavulanic acid and homovanillic acid were identified as potential lead compounds for the SARS-CoV-2 helicase. Molecular dynamics simulations were performed with the leads bound to the SARS-CoV-2 helicase for 200 ns in triplicate, with favourable binding free energies to the NTPase site. Given their availability, further exploration of their potential inhibitory activity could be considered.
Keywords: Antivirals; COVID-19; Helicase; SARS-CoV-2; nsp13.
【저자키워드】 COVID-19, SARS-CoV-2, antivirals, Helicase, nsp13., 【초록키워드】 coronavirus disease, Structure, Vaccine, coronavirus, SARS-CoV, variant, molecular dynamics, antiviral activity, molecular dynamics simulations, binding free energy, MERS-CoV, Molecular dynamics simulation, Helicase, nsp13, Severe acute respiratory syndrome, DNA, Hepatitis, Research, hepatitis C, non-structural protein, structural proteins, Acetylcysteine, antiviral therapeutics, respiratory, inhibitor, Fatty acid, synthetic, Ligand, structures, strain, leads, lead, fatty acids, active site, specific inhibitors, specific inhibitor, free energies, acute respiratory syndrome, clavulanic acid, Compound, sequence, nucleoside, inhibitory activity, structural homology, DHX9, DNA2, SARS-CoV-2 nsp13, initial, selected, identify, performed, include, reported, addition, was performed, were used, expected, highlighting, utilised, anti-inflammatory property, the SARS-CoV-2, 【제목키워드】 Antiviral, in silico, identification, small molecule inhibitor,