Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

Abstract

SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, −8.7 kcal/mol), PLpro (binding energy, −7.9 kcal/mol), and Nucleocapsid (binding energy, −7.9 kcal/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 Å), PLpro (mean RMSD, 0.96 Å), and Nucleocapsid (mean RMSD, 3.48 Å)). Moreover, binding free energy analyses such as MMGB/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, −24.42 kcal/mol and MMPBSA, −10.80 kcal/mol), PLpro (MMGBSA, −48.69 kcal/mol and MMPBSA, −38.17 kcal/mol) and Nucleocapsid (MMGBSA, −30.05 kcal/mol and MMPBSA, −25.95 kcal/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, −22.44 kcal/mol), PLpro (mean, −25.46 kcal/mol), and Nucleocapsid (mean, −23.30 kcal/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection.

Rutin Is a Low Micromolar Inhibitor of SARS-CoV-2 Main Protease 3CLpro: Implications for Drug Design of Quercetin Analogs

“…However, and despite the huge number of research studies reported so far, the development of safe and effective drugs able to block the viral infection is still lacking and represents a major goal for the scientific world. Among all the possible chemical compounds, particular attention has been dedicated to molecules of natural origin [5][6][7][8], including extracts, single bioactive molecules, or entire classes of phytochemicals targeting SARS-CoV-2, and several of them are currently under investigation.…”

Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations

“…Alamri et al utilized molecular docking and dynamic simulations to identify M pro candidates from Saudi medical plants 20 . Muhseen et al used the above two methods to identify M pro inhibitors from MPD3 phytochemical database 21 – 24 . Certain database-specific inhibitors search were also made including Super Natural II 25 , Marine Natural Product (MNP) 26 and Traditional Chinese Medicine 27 .…”

Screening Potential Drugs for COVID-19 Based on Bound Nuclear Norm Regularization

“…Mycophenolic acid is also an immunosuppressive drug with a strong anti-proliferation effect (Kim et al, 2019). Studies suggest that mycophenolic acid has a potential inhibitory effect on the enzyme reproduced by SARS-CoV-2 (Muhseen et al, 2021).…”