Identification of Persuasive Antiviral Natural Compounds for COVID-19 by Targeting Endoribonuclease NSP15: A Structural-Bioinformatics Approach

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-12, Vol.25 (23), p.5657
• Main Authors: Saeed, Mohd, Saeed, Amir, Alam, Md Jahoor, Alreshidi, Mousa
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Binding sites; Bioinformatics; Biosynthesis; Catalytic Domain; Coronaviruses; COVID-19; COVID-19 - drug therapy; Disease transmission; Ecophysiology; Endoribonucleases - chemistry; Endoribonucleases - metabolism; Genomes; High-throughput screening; High-Throughput Screening Assays - methods; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Intermediates; Ligands; Middle East respiratory syndrome; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; natural compounds; Natural products; Nonstructural proteins; NSP15; Optimization; Pandemics; Proteins; RNA viruses; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Simulation; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - metabolism; Virions; virtual screening; Viruses
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25235657

SARS-CoV-2 is a positive-stranded RNA virus that bundles its genomic material as messenger-sense RNA in infectious virions and replicates these genomes through RNA intermediates. Several virus-encoded nonstructural proteins play a key role during the viral life cycle. Endoribonuclease NSP15 is vital for the replication and life cycle of the virus, and is thus considered a compelling druggable target. Here, we performed a combination of multiscoring virtual screening and molecular docking of a library of 1624 natural compounds (Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products (NuBBE) database) on the active sites of NSP15 (PDB:6VWW). After sequential high-throughput screening by LibDock and GOLD, docking optimization by CDOCKER, and final scoring by calculating binding energies, top-ranked compounds NuBBE-1970 and NuBBE-242 were further investigated via an indepth molecular-docking and molecular-dynamics simulation of 60 ns, which revealed that the binding of these two compounds with active site residues of NSP15 was sufficiently strong and stable. The findings strongly suggest that further optimization and clinical investigations of these potent compounds may lead to effective SARS-CoV-2 treatment.