Multi-stage structure-based virtual screening approach towards identification of potential SARS-CoV-2 NSP13 helicase inhibitors

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 37; no. 1; pp. 563 - 572
• Main Authors: El Hassab, Mahmoud A., Eldehna, Wagdy M., Al-Rashood, Sara T., Alharbi, Amal, Eskandrani, Razan O., Alkahtani, Hamad M., Elkaeed, Eslam B., Abou-Seri, Sahar M.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.12.2022; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Binding sites; Catalytic Domain; Chemistry; Coronaviruses; COVID-19 - virology; COVID-19 Drug Treatment; COVID-19 vaccines; DNA helicase; docking; Drug Discovery; Enzymes; Exoribonucleases - antagonists & inhibitors; Free energy; High-Throughput Screening Assays - methods; Humans; Hypotheses; Infections; Life cycles; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; molecular dynamics simulations; Pharmaceuticals; Pharmacy; protein-ligand interaction fingerprint; Proteins; Quantitative Structure-Activity Relationship; Research Paper; RNA polymerase; SARS CoV-2 NSP13 helicase; SARS-CoV-2 - drug effects; Severe acute respiratory syndrome coronavirus 2; Simulation; Software; structure-based pharmacophore; Viral Nonstructural Proteins - antagonists & inhibitors; molecular dynamics simulations; docking; SARS CoV-2 NSP13 helicase; protein-ligand interaction fingerprint; structure-based pharmacophore
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2021.2022659

On account of its crucial role in the virus life cycle, SARS-COV-2 NSP13 helicase enzyme was exploited as a promising target to identify a novel potential inhibitor using multi-stage structure-based drug discovery approaches. Firstly, a 3D pharmacophore was generated based on the collected data from a protein-ligand interaction fingerprint (PLIF) study using key interactions between co-crystallised fragments and the NSP13 helicase active site. The ZINC database was screened through the generated 3D-pharmacophore retrieving 13 potential hits. All the retrieved hits exceeded the benchmark score of the co-crystallised fragments at the molecular docking step and the best five-hit compounds were selected for further analysis. Finally, a combination between molecular dynamics simulations and MM-PBSA based binding free energy calculations was conducted on the best hit (compound FWM-1) bound to NSP13 helicase enzyme, which identified FWM-1 as a potential potent NSP13 helicase inhibitor with binding free energy equals −328.6 ± 9.2 kcal/mol.