GC-MS, LC-MS/MS, Docking and Molecular Dynamics Approaches to Identify Potential SARS-CoV-2 3-Chymotrypsin-Like Protease Inhibitors from Zingiber officinale Roscoe

Abstract

This study aims to identify and isolate the secondary metabolites of Zingiber officinale using GC-MS, preparative TLC, and LC-MS/MS methods, to evaluate the inhibitory potency on SARS-CoV-2 3 chymotrypsin-like protease enzyme, as well as to study the molecular interaction and stability by using docking and molecular dynamics simulations. GC-MS analysis suggested for the isolation of terpenoids compounds as major compounds on methanol extract of pseudostems and rhizomes. Isolation and LC-MS/MS analysis identified 5-hydro-7, 8, 2′-trimethoxyflavanone (9), (E)-hexadecyl-ferulate (1), isocyperol (2), N-isobutyl-(2E,4E)-octadecadienamide (3), and nootkatone (4) from the rhizome extract, as well as from the leaves extract with the absence of 9. Three known steroid compounds, i.e., spinasterone (7), spinasterol (8), and 24-methylcholesta-7-en-3β-on (6), were further identified from the pseudostem extract. Molecular docking showed that steroids compounds 7, 8, and 6 have lower predictive binding energies (MMGBSA) than other metabolites with binding energy of −87.91, −78.11, and −68.80 kcal/mole, respectively. Further characterization on the single isolated compound by NMR showed that 6 was identified and possessed 75% inhibitory activity on SARS-CoV-2 3CL protease enzyme that was slightly different with the positive control GC376 (77%). MD simulations showed the complex stability with compound 6 during 100 ns simulation time.

Molecular Docking, Molecular Dynamics Simulations, and Free Energy Calculation Insights into the Binding Mechanism between VS-4718 and Focal Adhesion Kinase

“…The calculated binding free energies presented in Table show that the nonpolar (i.e., hydrophobic) term plays the most important role in complex formation. Because the per-residue free energy decomposition strategy is known to enable analysis of the inhibitor–protein interactions, ,− the interaction energies between the various residues of FAK and VS-4718 were computed using the MM/GBSA decomposition protocol (Tables S5 and S6). As indicated by the obtained results, several hydrophobic residues possessed substantial subtotal binding free energies.…”

Antiviral phytocompounds “ellagic acid” and “(+)-sesamin” of Bridelia retusa identified as potential inhibitors of SARS-CoV-2 3CL pro using extensive molecular docking, molecular dynamics simulation studies, binding free energy calculations, and bioactivity prediction

“…Molecular dynamics study was carried out on Linux Ubuntu 20.04.1 LTS 64-bit, NVIDIA Quadro P2200 graphic card, 16 GB RAM, and Intel Xeon(R) W-2223 @3.60 GHz octa-core processor with Desmond on Maestro Schrödinger 2021–2 [ 38 – 40 ]. The molecular dynamics protocol described by Zubair et al was followed [ 41 ]. MD process was commenced by generating complexes of the ligand–protein system from docking results and placing them in a cubic box at 10 Å solvating with SPC (simple point charge) water model.…”

The Interaction of Antiviral Drugs with SARS-Cov-2 3CL Protease

“…With increased strength, flavanols have mono or disaccharide substituted at position C3. NMR was used to identify inhibitors, and compound 6 exhibited 75% inhibitory activity against SARS-CoV-2 main proteinase (3CL Mpro) (Zubair et al, 2021;Klemm et al, 2021).…”