Identification of FDA-approved drugs against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) through computational virtual screening

• Published in: Structural chemistry 2023-06, Vol.34 (3), p.1005-1019
• Main Authors: Jade, Dhananjay, Alzahrani, Areej, Critchley, William, Ponnambalam, Sreenivasan, Harrison, Michael A.
• Format: Article
• Language: English
• Subjects: Binding energy; Chemical bonds; Chemical synthesis; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Coronaviruses; COVID-19; Drugs; FDA approval; Force and energy; Free energy; Hydrogen; Hydrogen bonds; Inhibitors; Molecular dynamics; Original Research; Physical Chemistry; Protein binding; Proteins; RNA; RNA polymerase; RNA polymerases; Screening; Severe acute respiratory syndrome coronavirus 2; Simulation; Substrates; Synthesis; Theoretical and Computational Chemistry; Viral diseases
• ISSN: 1040-0400; 1572-9001
• DOI: 10.1007/s11224-022-02072-1

The SARS-CoV-2 coronavirus is responsible for the COVID-19 outbreak, which overwhelmed millions of people worldwide; hence, there is an urgency to identify appropriate antiviral drugs. This study focuses on screening compounds that inhibit RNA-dependent RNA-polymerase (RdRp) essential for RNA synthesis required for replication of positive-strand RNA viruses. Computational screening against RdRp using Food and Drug Administration (FDA)-approved drugs identified ten prominent compounds with binding energies of more than − 10.00 kcal/mol, each a potential inhibitor of RdRp. These compounds’ binding energy is comparable to known RdRp inhibitors remdesivir (IC50 = 10.09 μM, SI = 4.96) and molnupiravir (EC50 = 0.67 − 2.66 µM) and 0.32–2.03 µM). Remdesivir and molnupiravir have been tested in clinical trial and remain authorized for emergency use in the treatment of COVID-19. In docking simulations, selected compounds are bound to the substrate-binding pocket of RdRp and showed hydrophobic and hydrogen bond interaction. For molecular dynamics simulation, capmatinib, pralsetinib, ponatinib, and tedizolid phosphate were selected from the initial ten candidate compounds. MD simulation indicated that these compounds are stable at 50-ns MD simulation when bound to RdRp protein. The screen hit compounds, remdesivir, molnupiravir, and GS-441524, are bound in the substrate binding pocket with good binding-free energy. As a consequence, capmatinib, pralsetinib, ponatinib, and tedizolid phosphate are potential new inhibitors of RdRp protein with potential of limiting COVID-19 infection by blocking RNA synthesis.